Parasitic infections contribute significantly to worldwide morbidity and mortality. Antibiotic tr... more Parasitic infections contribute significantly to worldwide morbidity and mortality. Antibiotic treatment is essential for managing patients infected with these parasites since control is otherwise challenging and there are no vaccines available for prevention. However, new antimicrobial therapies are urgently needed as significant problems exist with current treatments such as drug resistance, limited options, poor efficacy, as well as toxicity. This situation is made worse by the challenges of drug discovery and development which is costly especially for non-profitable infectious diseases, time-consuming, and risky with a high failure rate. Drug repurposing which involves finding new use for existing drugs may help to more rapidly identify therapeutic candidates while drastically cutting costs of drug research and development. In this perspective article, we discuss the importance of drug repurposing, review disulfiram pharmacology, and highlight emerging data that supports repurposing disulfiram as an anti-parasitic, exemplified by the major diarrhea-causing parasite Entamoeba histolytica.
Corticosteroid use is increasing worldwide as recent studies confer survival benefit of corticost... more Corticosteroid use is increasing worldwide as recent studies confer survival benefit of corticosteroids in the management of patients with severe COVID-19. Strongyloides and amebic infections are neglected diseases that can progress to catastrophic complications in patients exposed to corticosteroids, even with short treatment courses. To prevent lethal outcomes, clinicians should be aware of the threat these two parasitic infections pose to at-risk patients receiving corticosteroids, especially in the era of COVID-19.
We describe 4 children (11-17 years in age) at our institution with acute appendicitis in the set... more We describe 4 children (11-17 years in age) at our institution with acute appendicitis in the setting of SARS-CoV-2 infection, suggesting a possible association. Providers should consider testing for this infection in patients with severe gastrointestinal symptoms, in order to take appropriate transmission based precautions, until more is understood.
This article provides new insights into parasite protein degradation regulation, target for drug ... more This article provides new insights into parasite protein degradation regulation, target for drug discovery, and potential repurposing of FDA-approved drug disulfiram.
We report a case of Entamoeba histolytica infection in a young man who presented with cerebral in... more We report a case of Entamoeba histolytica infection in a young man who presented with cerebral infarction and shortly after admission developed bloody diarrhea with fever. A rapid diagnosis of severe E. histolytica colitis was established through the use of a multiplex polymerase chain reaction enteropathogen stool panel. This result was unexpected in a patient native to the United States without known risk factors for amebiasis and negative stool mi-croscopy examination for ova and parasites. Rapid diagnosis allowed prompt initiation of appropriate anti-amebic therapy and ultimately a good outcome in a condition that otherwise carries high morbidity and fatality.
Wound healing after an injury is essential for life. An in-depth understanding of the healing pro... more Wound healing after an injury is essential for life. An in-depth understanding of the healing process is necessary to ultimately improve the currently limited treatment options for patients suffering as a result of damage to various organs and tissues. Injuries, even the most minor, trigger an inflammatory response that protects the host and activates repair pathways. In recent years, substantial progress has been made in delineating the mechanisms by which inflammatory cytokines and their receptors facilitate tissue repair and regeneration. This mini review focuses on emerging literature on the role of the cytokine macrophage migration inhibitory factor (MIF) and its cell membrane receptor CD74, in protecting against injury and promoting healing in different parts of the body.
In this study, we uncovered a mechanistic link between intestinal inflammation and repair. We sho... more In this study, we uncovered a mechanistic link between intestinal inflammation and repair. We showed that cluster of differentiation 74 (CD74, MIF cytokine receptor) signaling is strongly activated during intestinal inflammation, and promotes mucosal healing by enhancing intestinal epithelial cell proliferation by activating the protein kinase B (Akt) and extracellular signal-regulated ki-nase (ERK) pathways.
In this study, we uncovered a mechanistic link between intestinal inflammation and repair. We sho... more In this study, we uncovered a mechanistic link between intestinal inflammation and repair. We showed that cluster of differentiation 74 (CD74) signaling is strongly activated during intestinal inflammation, and promotes mucosal healing by enhancing intestinal epithelial cell proliferation by activating the protein kinase B (Akt) and extracellular signal-regulated kinase (ERK) pathways.
Amebiasis, due to the pathogenic parasite Entamoeba histolytica, is a leading cause of diarrhea g... more Amebiasis, due to the pathogenic parasite Entamoeba histolytica, is a leading cause of diarrhea globally. Largely an infection of impoverished communities in developing countries, amebiasis has emerged as an important infection among returning travelers, immigrants, and men who have sex with men residing in developed countries. Severe cases can be associated with high case fatality. Polymerase chain reaction-based diagnosis is increasingly available but remains underutilized. Nitroimidazoles are currently recommended for treatment, but new drug development to treat parasitic agents is a high priority. Amebiasis should be considered before corticosteroid therapy to decrease complications. There is no effective vaccine, so prevention focuses on sanitation and access to clean water. Further understanding of parasite biology and pathogenesis will advance future targeted therapeutic and preventative strategies. Amebiasis is caused by infection with the pseudopod-forming , nonflagellated protozoan parasite Entamoeba histolytica. Amebiasis can be asymptomatic or can lead to the development of severe infection with amebic colitis and amebic liver abscess. The significance of amebiasis is exemplified in several ways. Amebic colitis is a leading cause of severe diarrhea worldwide and is listed among the top 15 causes of diarrhea in the first 2 years of life in children living in the developing world, where diarrhea remains the third leading cause of death, accounting for 9% of all deaths in children under the age of 5 years [1-3]. Fulminant amebic colitis is an uncommon complication of amebiasis but is associated with high mortality , and on average more than 50% with severe colitis die [4]. E. histolytica is classified as a category B priority biodefense pathogen by the National Institute of Allergy and Infectious Diseases (NIAID) because of its low infectious dose, chlorine resistance, and environmental stability, properties that can pose a threat of easy dissemination through contamination of food and water supplies. Even in low-incidence settings, these properties of the parasite lead to outbreaks among military and general populations [5-7]. In addition, E. histolytica is one of the most common causes of infectious diarrhea among travelers returning from endemic areas [8]. Advances in molecular diagnostic methodologies have improved our understanding and led to the recognition and separation of E. histolytica from nonpathogenic species of Entamoeba. Of the many Entamoeba species that infect humans, 3 species are morphologically indistinguishable from E. histolytica. Of these 3, E. moshkovskii may cause diarrhea, whereas E. dispar and the newly described E. bangladeshi are considered nonpathogenic [9]. Earlier descriptions of ameb-iasis relying solely on microscopy may have been obscured by these nonpathogenic strains. There is no vaccine to prevent amebiasis. Nitroimidazoles are the mainstay treatment for invasive amebiasis. Given the toxicity that can be associated with this class and potential concerns for development of resistance, as has already been reported for some anaerobic pathogens, new therapies are needed [10]. In addition, the NIAID has set priorities for drug development for treatment of category B pathogens. For these reasons, improved understanding of amebiasis pathogenesis is needed as a way forward toward enhanced treatment and prevention. This report reviews recent literature expanding our knowledge of the epidemiology , clinical presentation, and management of ameb-iasis, while providing important new insights into diagnostic evaluation and prevention. EPIDEMIOLOGY Global Burden The global significance of amebiasis is widespread, with the highest burden of amebiasis borne by those residing in developing countries, particularly the tropics and subtropics, where there is inadequate hygiene and access to sanitation. Millions
Targeting virulence factors represents a promising alternative approach to antimicrobial therapy,... more Targeting virulence factors represents a promising alternative approach to antimicrobial therapy, through the inhibition of pathogenic pathways that result in host tissue damage. Yet, virulence inhibition remains an understudied area in para-sitology. Several medically important protozoan parasites such as Plasmodium, Entamoeba, Toxoplasma, and Leishmania secrete an inflammatory macrophage migration inhibitory factor (MIF) cytokine homolog, a virulence factor linked to severe disease. The aim of this study was to investigate the effectiveness of targeting parasite-produced MIF as combination therapy with standard antibiotics to reduce disease severity. Here, we used Entamoeba histolytica as the model MIF-secreting protozoan, and a mouse model that mirrors severe human infection. We found that intestinal inflammation and tissue damage were significantly reduced in mice treated with metronidazole when combined with anti-E. histolytica MIF antibodies, compared to metronidazole alone. Thus, this preclinical study provides proof-of-concept that combining antiparasite MIF-blocking antibodies with current standard-of-care antibiotics might improve outcomes in severe proto-zoan infections.
We report a case of Entamoeba histolytica infection in a young man who presented with cerebral in... more We report a case of Entamoeba histolytica infection in a young man who presented with cerebral infarction and shortly after admission developed bloody diarrhea with fever. A rapid diagnosis of severe E. histolytica colitis was established through the use of a multiplex polymerase chain reaction enteropathogen stool panel. This result was unexpected in a patient native to the United States without known risk factors for amebiasis and negative stool mi-croscopy examination for ova and parasites. Rapid diagnosis allowed prompt initiation of appropriate anti-amebic therapy and ultimately a good outcome in a condition that otherwise carries high morbidity and fatality.
Macrophage migration inhibitory factor (MIF) is a proinflammatory and proproliferative cytokine e... more Macrophage migration inhibitory factor (MIF) is a proinflammatory and proproliferative cytokine expressed in humans. MIF homologs also exist in many pathogenic protozoans, including Entamoeba, Plasmodium, Toxoplasma, and Leishmania. Production of antibodies against parasite proteins allows for the generation of assays to measure and visualize parasite infection within hosts. In this chapter, we describe how to specifically purify antibodies against Entamoeba histolytica MIF (EhMIF), and subsequently use anti-EhMIF antibodies for ELISA on mouse and human samples and for immunohistochemistry on human tissue. These methods can be applied to any protein for high-quality antibody purification.
Targeting virulence factors represents a promising alternative approach to antimicrobial therapy,... more Targeting virulence factors represents a promising alternative approach to antimicrobial therapy, through the inhibition of pathogenic pathways that result in host tissue damage. Yet, virulence inhibition remains an understudied area in parasitology. Several medically important protozoan parasites such as Plasmodium, Entamoeba, Toxoplasma, and Leishmania secrete an inflammatory macrophage migration inhibitory factor (MIF) cytokine homolog, a virulence factor linked to severe disease. The aim of this study was to investigate the effectiveness of targeting parasite-produced MIF as combination therapy with standard antibiotics to reduce disease severity. Here, we used Entamoeba histolytica as the model MIF-secreting protozoan, and a mouse model that mirrors severe human infection. We found that intestinal inflammation and tissue damage were significantly reduced in mice treated with metronidazole when combined with anti–E. histolytica MIF antibodies, compared to metronidazole alone. Thus, this preclinical study provides proof-of-concept that combining antiparasite MIF-blocking antibodies with current standard-of-care antibiotics might improve outcomes in severe protozoan infections.
The significance of amebiasis is a global problem, with prevalence that may reach as high as 40% ... more The significance of amebiasis is a global problem, with prevalence that may reach as high as 40% in some areas of the world. Disease can be severe and fatal in some, but there are no accurate disease prevalence estimates to help define the true burden. Transmission is fecal–oral and so cannot easily be prevented when there is poverty, inadequate sanitation, and insufficient hygiene. Globalization, immigration, international travel, and sexual practices place everyone at risk of infection. The hardiness of the cyst further lends to ease of spread, predisposing to risks of epidemics among military, the general population, and even as a potential biological threat. The emergence of hypervirulent strains has been newly reported. Treatment options are limited, and there are no other reliably effective options if resistance develops to the nitroimidazole agents, as has already been documented with other protozoan parasites treated by this class of drugs. We still lack a viable vaccine candidate ready to enter into clinical development. Funding agencies dedicated to support research in neglected tropical diseases control should include E. histolytica as a priority pathogen in order to encourage the development of new innovative technologies for diagnosis, discovery of new drug targets, and strategies for control, including vaccine development. Now is the time to stop neglecting amebiasis.
Protozoan parasites represent a major threat to health and contribute significantly to morbidity ... more Protozoan parasites represent a major threat to health and contribute significantly to morbidity and mortality worldwide, especially in developing countries. This is further compounded by lack of effective vaccines, drug resistance and toxicity associated with current therapies. Multiple protozoans, including Plasmodium, Entamoeba, Toxoplasma, and Leishmania produce homologs of the cytokine MIF. These parasite MIF homologs are capable of altering the host immune response during infection, and play a role in immune evasion, invasion and pathogenesis. This minireview outlines well-established and emerging literature on the role of parasite MIF homologs in disease, and their potential as targets for therapeutic and preventive interventions.
Purpose of Review
Entamoeba histolytica is a protozoan parasite that causes amebiasis, which rema... more Purpose of Review Entamoeba histolytica is a protozoan parasite that causes amebiasis, which remains a significant cause of morbidity and mortality worldwide. E. histolytica causes tissue destruction which leads to clinical disease. This review outlines some of the recent advances that have furthered our understanding of the processes that lead to the tissue damage caused by E. histolytica.
Recent Findings Recent studies have identified new mechanisms involved in E. histolytica–induced tissue damage. These include (i) new form of contact-dependent killing called trogocytosis; (ii) parasite-produced cytokine, macrophage migration inhibitory factor, that contributes to inflammation; (iii) exploitation of host immune response to promote invasion; and (iv) the contribution of the gut microbiome to clinical disease.
Summary Targeting these mechanisms that result in tissue injury should be a focus of future research for the development of improved preventive and therapeutic strategies for amebiasis.
Understanding the mechanisms by which Entamoeba histolytica drives gut inflammation is critical f... more Understanding the mechanisms by which Entamoeba histolytica drives gut inflammation is critical for the development of improved preventive and therapeutic strategies. E. histolytica encodes a homolog of the human cytokine macrophage migration inhibitory factor (MIF). Here, we investigated the role of E. histolytica MIF (EhMIF) during infection. We found that the concentration of fecal EhMIF correlated with the level of intestinal inflammation in persons with intestinal amebiasis. Mice treated with antibodies that specifically block EhMIF had reduced chemokine expression and neutrophil infiltration in the mucosa. In addition to antibody-mediated neutralization, we used a genetic approach to test the effect of EhMIF on mucosal inflammation. Mice infected with parasites overexpressing EhMIF had increased chemokine expression, neutrophil influx, and mucosal damage. Together, these results uncover a specific parasite protein that increases mucosal inflammation, expands our knowledge of host–parasite interaction during amebic colitis, and highlights a potential immunomodulatory target.
Amebiasis, due to the pathogenic parasite Entamoeba histolytica, is a leading cause of diarrhea g... more Amebiasis, due to the pathogenic parasite Entamoeba histolytica, is a leading cause of diarrhea globally. Largely an infection of impoverished communities in developing countries, amebiasis has emerged as an important infection among returning travelers, immigrants, and men who have sex with men residing in developed countries. Severe cases can be associated with high case fatality. Polymerase chain reaction–based diagnosis is increasingly available but remains underutilized. Nitroimidazoles are currently recommended for treatment, but new drug development to treat parasitic agents is a high priority. Amebiasis should be considered before corticosteroid therapy to decrease complications. There is no effective vaccine, so prevention focuses on sanitation and access to clean water. Further understanding of parasite biology and pathogenesis will advance future targeted therapeutic and preventative strategies.
Entamoeba histolytica is one of the most important enteric pathogens affecting people worldwide, ... more Entamoeba histolytica is one of the most important enteric pathogens affecting people worldwide, causing the diarrheal disease amebic colitis. Fulminant amebic colitis is an uncommon but life threatening complication that may ensue. High rates of colonization with E. histolytica burden many developing countries, and travelers are at risk of acquisition of infection when they visit endemic areas. Corticosteroids are an invaluable group of broadly prescribed anti-inflammatory medications, but have been identified as a risk factor for the development of fulminant amebic colitis. Our comprehensive report highlights the frequent misdiagnosis of amebic colitis and the high morbidity and mortality associated with fulminant disease. Improved awareness of this condition among medical providers is needed, so that infection with E. histolytica can be considered in both patients presenting with symptoms of colitis and patients with asymptomatic colonization prior to the administration of corticosteroids. This study points to the need to continue efforts to develop both a vaccine that can prevent amebic colitis and innovative life- and bowel-saving adjuncts for the treatment of fulminant amebic colitis through an improved understanding of host responses to infection with E. histolytica.
Tissue Destruction Caused by Entamoeba histolytica Parasite: Cell Death, Inflammation, Invasion, and the Gut Microbiome
Purpose of Review
Entamoeba histolytica is a protozoan parasite that causes amebiasis, which rema... more Purpose of Review Entamoeba histolytica is a protozoan parasite that causes amebiasis, which remains a significant cause of morbidity and mortality worldwide. E. histolytica causes tissue destruction which leads to clinical disease. This review outlines some of the recent advances that have furthered our understanding of the processes that lead to the tissue damage caused by E. histolytica.
Recent Findings Recent studies have identified new mechanisms involved in E. histolytica–induced tissue damage. These include (i) new form of contact-dependent killing called trogocytosis; (ii) parasite-produced cytokine, macrophage migration inhibitory factor, that contributes to inflammation; (iii) exploitation of host immune response to promote invasion; and (iv) the contribution of the gut microbiome to clinical disease.
Summary Targeting these mechanisms that result in tissue injury should be a focus of future research for the development of improved preventive and therapeutic strategies for amebiasis.
Parasitic infections contribute significantly to worldwide morbidity and mortality. Antibiotic tr... more Parasitic infections contribute significantly to worldwide morbidity and mortality. Antibiotic treatment is essential for managing patients infected with these parasites since control is otherwise challenging and there are no vaccines available for prevention. However, new antimicrobial therapies are urgently needed as significant problems exist with current treatments such as drug resistance, limited options, poor efficacy, as well as toxicity. This situation is made worse by the challenges of drug discovery and development which is costly especially for non-profitable infectious diseases, time-consuming, and risky with a high failure rate. Drug repurposing which involves finding new use for existing drugs may help to more rapidly identify therapeutic candidates while drastically cutting costs of drug research and development. In this perspective article, we discuss the importance of drug repurposing, review disulfiram pharmacology, and highlight emerging data that supports repurposing disulfiram as an anti-parasitic, exemplified by the major diarrhea-causing parasite Entamoeba histolytica.
Corticosteroid use is increasing worldwide as recent studies confer survival benefit of corticost... more Corticosteroid use is increasing worldwide as recent studies confer survival benefit of corticosteroids in the management of patients with severe COVID-19. Strongyloides and amebic infections are neglected diseases that can progress to catastrophic complications in patients exposed to corticosteroids, even with short treatment courses. To prevent lethal outcomes, clinicians should be aware of the threat these two parasitic infections pose to at-risk patients receiving corticosteroids, especially in the era of COVID-19.
We describe 4 children (11-17 years in age) at our institution with acute appendicitis in the set... more We describe 4 children (11-17 years in age) at our institution with acute appendicitis in the setting of SARS-CoV-2 infection, suggesting a possible association. Providers should consider testing for this infection in patients with severe gastrointestinal symptoms, in order to take appropriate transmission based precautions, until more is understood.
This article provides new insights into parasite protein degradation regulation, target for drug ... more This article provides new insights into parasite protein degradation regulation, target for drug discovery, and potential repurposing of FDA-approved drug disulfiram.
We report a case of Entamoeba histolytica infection in a young man who presented with cerebral in... more We report a case of Entamoeba histolytica infection in a young man who presented with cerebral infarction and shortly after admission developed bloody diarrhea with fever. A rapid diagnosis of severe E. histolytica colitis was established through the use of a multiplex polymerase chain reaction enteropathogen stool panel. This result was unexpected in a patient native to the United States without known risk factors for amebiasis and negative stool mi-croscopy examination for ova and parasites. Rapid diagnosis allowed prompt initiation of appropriate anti-amebic therapy and ultimately a good outcome in a condition that otherwise carries high morbidity and fatality.
Wound healing after an injury is essential for life. An in-depth understanding of the healing pro... more Wound healing after an injury is essential for life. An in-depth understanding of the healing process is necessary to ultimately improve the currently limited treatment options for patients suffering as a result of damage to various organs and tissues. Injuries, even the most minor, trigger an inflammatory response that protects the host and activates repair pathways. In recent years, substantial progress has been made in delineating the mechanisms by which inflammatory cytokines and their receptors facilitate tissue repair and regeneration. This mini review focuses on emerging literature on the role of the cytokine macrophage migration inhibitory factor (MIF) and its cell membrane receptor CD74, in protecting against injury and promoting healing in different parts of the body.
In this study, we uncovered a mechanistic link between intestinal inflammation and repair. We sho... more In this study, we uncovered a mechanistic link between intestinal inflammation and repair. We showed that cluster of differentiation 74 (CD74, MIF cytokine receptor) signaling is strongly activated during intestinal inflammation, and promotes mucosal healing by enhancing intestinal epithelial cell proliferation by activating the protein kinase B (Akt) and extracellular signal-regulated ki-nase (ERK) pathways.
In this study, we uncovered a mechanistic link between intestinal inflammation and repair. We sho... more In this study, we uncovered a mechanistic link between intestinal inflammation and repair. We showed that cluster of differentiation 74 (CD74) signaling is strongly activated during intestinal inflammation, and promotes mucosal healing by enhancing intestinal epithelial cell proliferation by activating the protein kinase B (Akt) and extracellular signal-regulated kinase (ERK) pathways.
Amebiasis, due to the pathogenic parasite Entamoeba histolytica, is a leading cause of diarrhea g... more Amebiasis, due to the pathogenic parasite Entamoeba histolytica, is a leading cause of diarrhea globally. Largely an infection of impoverished communities in developing countries, amebiasis has emerged as an important infection among returning travelers, immigrants, and men who have sex with men residing in developed countries. Severe cases can be associated with high case fatality. Polymerase chain reaction-based diagnosis is increasingly available but remains underutilized. Nitroimidazoles are currently recommended for treatment, but new drug development to treat parasitic agents is a high priority. Amebiasis should be considered before corticosteroid therapy to decrease complications. There is no effective vaccine, so prevention focuses on sanitation and access to clean water. Further understanding of parasite biology and pathogenesis will advance future targeted therapeutic and preventative strategies. Amebiasis is caused by infection with the pseudopod-forming , nonflagellated protozoan parasite Entamoeba histolytica. Amebiasis can be asymptomatic or can lead to the development of severe infection with amebic colitis and amebic liver abscess. The significance of amebiasis is exemplified in several ways. Amebic colitis is a leading cause of severe diarrhea worldwide and is listed among the top 15 causes of diarrhea in the first 2 years of life in children living in the developing world, where diarrhea remains the third leading cause of death, accounting for 9% of all deaths in children under the age of 5 years [1-3]. Fulminant amebic colitis is an uncommon complication of amebiasis but is associated with high mortality , and on average more than 50% with severe colitis die [4]. E. histolytica is classified as a category B priority biodefense pathogen by the National Institute of Allergy and Infectious Diseases (NIAID) because of its low infectious dose, chlorine resistance, and environmental stability, properties that can pose a threat of easy dissemination through contamination of food and water supplies. Even in low-incidence settings, these properties of the parasite lead to outbreaks among military and general populations [5-7]. In addition, E. histolytica is one of the most common causes of infectious diarrhea among travelers returning from endemic areas [8]. Advances in molecular diagnostic methodologies have improved our understanding and led to the recognition and separation of E. histolytica from nonpathogenic species of Entamoeba. Of the many Entamoeba species that infect humans, 3 species are morphologically indistinguishable from E. histolytica. Of these 3, E. moshkovskii may cause diarrhea, whereas E. dispar and the newly described E. bangladeshi are considered nonpathogenic [9]. Earlier descriptions of ameb-iasis relying solely on microscopy may have been obscured by these nonpathogenic strains. There is no vaccine to prevent amebiasis. Nitroimidazoles are the mainstay treatment for invasive amebiasis. Given the toxicity that can be associated with this class and potential concerns for development of resistance, as has already been reported for some anaerobic pathogens, new therapies are needed [10]. In addition, the NIAID has set priorities for drug development for treatment of category B pathogens. For these reasons, improved understanding of amebiasis pathogenesis is needed as a way forward toward enhanced treatment and prevention. This report reviews recent literature expanding our knowledge of the epidemiology , clinical presentation, and management of ameb-iasis, while providing important new insights into diagnostic evaluation and prevention. EPIDEMIOLOGY Global Burden The global significance of amebiasis is widespread, with the highest burden of amebiasis borne by those residing in developing countries, particularly the tropics and subtropics, where there is inadequate hygiene and access to sanitation. Millions
Targeting virulence factors represents a promising alternative approach to antimicrobial therapy,... more Targeting virulence factors represents a promising alternative approach to antimicrobial therapy, through the inhibition of pathogenic pathways that result in host tissue damage. Yet, virulence inhibition remains an understudied area in para-sitology. Several medically important protozoan parasites such as Plasmodium, Entamoeba, Toxoplasma, and Leishmania secrete an inflammatory macrophage migration inhibitory factor (MIF) cytokine homolog, a virulence factor linked to severe disease. The aim of this study was to investigate the effectiveness of targeting parasite-produced MIF as combination therapy with standard antibiotics to reduce disease severity. Here, we used Entamoeba histolytica as the model MIF-secreting protozoan, and a mouse model that mirrors severe human infection. We found that intestinal inflammation and tissue damage were significantly reduced in mice treated with metronidazole when combined with anti-E. histolytica MIF antibodies, compared to metronidazole alone. Thus, this preclinical study provides proof-of-concept that combining antiparasite MIF-blocking antibodies with current standard-of-care antibiotics might improve outcomes in severe proto-zoan infections.
We report a case of Entamoeba histolytica infection in a young man who presented with cerebral in... more We report a case of Entamoeba histolytica infection in a young man who presented with cerebral infarction and shortly after admission developed bloody diarrhea with fever. A rapid diagnosis of severe E. histolytica colitis was established through the use of a multiplex polymerase chain reaction enteropathogen stool panel. This result was unexpected in a patient native to the United States without known risk factors for amebiasis and negative stool mi-croscopy examination for ova and parasites. Rapid diagnosis allowed prompt initiation of appropriate anti-amebic therapy and ultimately a good outcome in a condition that otherwise carries high morbidity and fatality.
Macrophage migration inhibitory factor (MIF) is a proinflammatory and proproliferative cytokine e... more Macrophage migration inhibitory factor (MIF) is a proinflammatory and proproliferative cytokine expressed in humans. MIF homologs also exist in many pathogenic protozoans, including Entamoeba, Plasmodium, Toxoplasma, and Leishmania. Production of antibodies against parasite proteins allows for the generation of assays to measure and visualize parasite infection within hosts. In this chapter, we describe how to specifically purify antibodies against Entamoeba histolytica MIF (EhMIF), and subsequently use anti-EhMIF antibodies for ELISA on mouse and human samples and for immunohistochemistry on human tissue. These methods can be applied to any protein for high-quality antibody purification.
Targeting virulence factors represents a promising alternative approach to antimicrobial therapy,... more Targeting virulence factors represents a promising alternative approach to antimicrobial therapy, through the inhibition of pathogenic pathways that result in host tissue damage. Yet, virulence inhibition remains an understudied area in parasitology. Several medically important protozoan parasites such as Plasmodium, Entamoeba, Toxoplasma, and Leishmania secrete an inflammatory macrophage migration inhibitory factor (MIF) cytokine homolog, a virulence factor linked to severe disease. The aim of this study was to investigate the effectiveness of targeting parasite-produced MIF as combination therapy with standard antibiotics to reduce disease severity. Here, we used Entamoeba histolytica as the model MIF-secreting protozoan, and a mouse model that mirrors severe human infection. We found that intestinal inflammation and tissue damage were significantly reduced in mice treated with metronidazole when combined with anti–E. histolytica MIF antibodies, compared to metronidazole alone. Thus, this preclinical study provides proof-of-concept that combining antiparasite MIF-blocking antibodies with current standard-of-care antibiotics might improve outcomes in severe protozoan infections.
The significance of amebiasis is a global problem, with prevalence that may reach as high as 40% ... more The significance of amebiasis is a global problem, with prevalence that may reach as high as 40% in some areas of the world. Disease can be severe and fatal in some, but there are no accurate disease prevalence estimates to help define the true burden. Transmission is fecal–oral and so cannot easily be prevented when there is poverty, inadequate sanitation, and insufficient hygiene. Globalization, immigration, international travel, and sexual practices place everyone at risk of infection. The hardiness of the cyst further lends to ease of spread, predisposing to risks of epidemics among military, the general population, and even as a potential biological threat. The emergence of hypervirulent strains has been newly reported. Treatment options are limited, and there are no other reliably effective options if resistance develops to the nitroimidazole agents, as has already been documented with other protozoan parasites treated by this class of drugs. We still lack a viable vaccine candidate ready to enter into clinical development. Funding agencies dedicated to support research in neglected tropical diseases control should include E. histolytica as a priority pathogen in order to encourage the development of new innovative technologies for diagnosis, discovery of new drug targets, and strategies for control, including vaccine development. Now is the time to stop neglecting amebiasis.
Protozoan parasites represent a major threat to health and contribute significantly to morbidity ... more Protozoan parasites represent a major threat to health and contribute significantly to morbidity and mortality worldwide, especially in developing countries. This is further compounded by lack of effective vaccines, drug resistance and toxicity associated with current therapies. Multiple protozoans, including Plasmodium, Entamoeba, Toxoplasma, and Leishmania produce homologs of the cytokine MIF. These parasite MIF homologs are capable of altering the host immune response during infection, and play a role in immune evasion, invasion and pathogenesis. This minireview outlines well-established and emerging literature on the role of parasite MIF homologs in disease, and their potential as targets for therapeutic and preventive interventions.
Purpose of Review
Entamoeba histolytica is a protozoan parasite that causes amebiasis, which rema... more Purpose of Review Entamoeba histolytica is a protozoan parasite that causes amebiasis, which remains a significant cause of morbidity and mortality worldwide. E. histolytica causes tissue destruction which leads to clinical disease. This review outlines some of the recent advances that have furthered our understanding of the processes that lead to the tissue damage caused by E. histolytica.
Recent Findings Recent studies have identified new mechanisms involved in E. histolytica–induced tissue damage. These include (i) new form of contact-dependent killing called trogocytosis; (ii) parasite-produced cytokine, macrophage migration inhibitory factor, that contributes to inflammation; (iii) exploitation of host immune response to promote invasion; and (iv) the contribution of the gut microbiome to clinical disease.
Summary Targeting these mechanisms that result in tissue injury should be a focus of future research for the development of improved preventive and therapeutic strategies for amebiasis.
Understanding the mechanisms by which Entamoeba histolytica drives gut inflammation is critical f... more Understanding the mechanisms by which Entamoeba histolytica drives gut inflammation is critical for the development of improved preventive and therapeutic strategies. E. histolytica encodes a homolog of the human cytokine macrophage migration inhibitory factor (MIF). Here, we investigated the role of E. histolytica MIF (EhMIF) during infection. We found that the concentration of fecal EhMIF correlated with the level of intestinal inflammation in persons with intestinal amebiasis. Mice treated with antibodies that specifically block EhMIF had reduced chemokine expression and neutrophil infiltration in the mucosa. In addition to antibody-mediated neutralization, we used a genetic approach to test the effect of EhMIF on mucosal inflammation. Mice infected with parasites overexpressing EhMIF had increased chemokine expression, neutrophil influx, and mucosal damage. Together, these results uncover a specific parasite protein that increases mucosal inflammation, expands our knowledge of host–parasite interaction during amebic colitis, and highlights a potential immunomodulatory target.
Amebiasis, due to the pathogenic parasite Entamoeba histolytica, is a leading cause of diarrhea g... more Amebiasis, due to the pathogenic parasite Entamoeba histolytica, is a leading cause of diarrhea globally. Largely an infection of impoverished communities in developing countries, amebiasis has emerged as an important infection among returning travelers, immigrants, and men who have sex with men residing in developed countries. Severe cases can be associated with high case fatality. Polymerase chain reaction–based diagnosis is increasingly available but remains underutilized. Nitroimidazoles are currently recommended for treatment, but new drug development to treat parasitic agents is a high priority. Amebiasis should be considered before corticosteroid therapy to decrease complications. There is no effective vaccine, so prevention focuses on sanitation and access to clean water. Further understanding of parasite biology and pathogenesis will advance future targeted therapeutic and preventative strategies.
Entamoeba histolytica is one of the most important enteric pathogens affecting people worldwide, ... more Entamoeba histolytica is one of the most important enteric pathogens affecting people worldwide, causing the diarrheal disease amebic colitis. Fulminant amebic colitis is an uncommon but life threatening complication that may ensue. High rates of colonization with E. histolytica burden many developing countries, and travelers are at risk of acquisition of infection when they visit endemic areas. Corticosteroids are an invaluable group of broadly prescribed anti-inflammatory medications, but have been identified as a risk factor for the development of fulminant amebic colitis. Our comprehensive report highlights the frequent misdiagnosis of amebic colitis and the high morbidity and mortality associated with fulminant disease. Improved awareness of this condition among medical providers is needed, so that infection with E. histolytica can be considered in both patients presenting with symptoms of colitis and patients with asymptomatic colonization prior to the administration of corticosteroids. This study points to the need to continue efforts to develop both a vaccine that can prevent amebic colitis and innovative life- and bowel-saving adjuncts for the treatment of fulminant amebic colitis through an improved understanding of host responses to infection with E. histolytica.
Tissue Destruction Caused by Entamoeba histolytica Parasite: Cell Death, Inflammation, Invasion, and the Gut Microbiome
Purpose of Review
Entamoeba histolytica is a protozoan parasite that causes amebiasis, which rema... more Purpose of Review Entamoeba histolytica is a protozoan parasite that causes amebiasis, which remains a significant cause of morbidity and mortality worldwide. E. histolytica causes tissue destruction which leads to clinical disease. This review outlines some of the recent advances that have furthered our understanding of the processes that lead to the tissue damage caused by E. histolytica.
Recent Findings Recent studies have identified new mechanisms involved in E. histolytica–induced tissue damage. These include (i) new form of contact-dependent killing called trogocytosis; (ii) parasite-produced cytokine, macrophage migration inhibitory factor, that contributes to inflammation; (iii) exploitation of host immune response to promote invasion; and (iv) the contribution of the gut microbiome to clinical disease.
Summary Targeting these mechanisms that result in tissue injury should be a focus of future research for the development of improved preventive and therapeutic strategies for amebiasis.
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Entamoeba histolytica is a protozoan parasite that causes amebiasis, which remains a significant cause of morbidity and mortality worldwide. E. histolytica causes tissue destruction which leads to clinical disease. This review outlines some of the recent advances that have furthered our understanding of the processes that lead to the tissue damage caused by E. histolytica.
Recent Findings
Recent studies have identified new mechanisms involved in E. histolytica–induced tissue damage. These include (i) new form of contact-dependent killing called trogocytosis; (ii) parasite-produced cytokine, macrophage migration inhibitory factor, that contributes to inflammation; (iii) exploitation of host immune response to promote invasion; and (iv) the contribution of the gut microbiome to clinical disease.
Summary
Targeting these mechanisms that result in tissue injury should be a focus of future research for the development of improved preventive and therapeutic strategies for amebiasis.
Entamoeba histolytica is a protozoan parasite that causes amebiasis, which remains a significant cause of morbidity and mortality worldwide. E. histolytica causes tissue destruction which leads to clinical disease. This review outlines some of the recent advances that have furthered our understanding of the processes that lead to the tissue damage caused by E. histolytica.
Recent Findings
Recent studies have identified new mechanisms involved in E. histolytica–induced tissue damage. These include (i) new form of contact-dependent killing called trogocytosis; (ii) parasite-produced cytokine, macrophage migration inhibitory factor, that contributes to inflammation; (iii) exploitation of host immune response to promote invasion; and (iv) the contribution of the gut microbiome to clinical disease.
Summary
Targeting these mechanisms that result in tissue injury should be a focus of future research for the development of improved preventive and therapeutic strategies for amebiasis.
Entamoeba histolytica is a protozoan parasite that causes amebiasis, which remains a significant cause of morbidity and mortality worldwide. E. histolytica causes tissue destruction which leads to clinical disease. This review outlines some of the recent advances that have furthered our understanding of the processes that lead to the tissue damage caused by E. histolytica.
Recent Findings
Recent studies have identified new mechanisms involved in E. histolytica–induced tissue damage. These include (i) new form of contact-dependent killing called trogocytosis; (ii) parasite-produced cytokine, macrophage migration inhibitory factor, that contributes to inflammation; (iii) exploitation of host immune response to promote invasion; and (iv) the contribution of the gut microbiome to clinical disease.
Summary
Targeting these mechanisms that result in tissue injury should be a focus of future research for the development of improved preventive and therapeutic strategies for amebiasis.
Entamoeba histolytica is a protozoan parasite that causes amebiasis, which remains a significant cause of morbidity and mortality worldwide. E. histolytica causes tissue destruction which leads to clinical disease. This review outlines some of the recent advances that have furthered our understanding of the processes that lead to the tissue damage caused by E. histolytica.
Recent Findings
Recent studies have identified new mechanisms involved in E. histolytica–induced tissue damage. These include (i) new form of contact-dependent killing called trogocytosis; (ii) parasite-produced cytokine, macrophage migration inhibitory factor, that contributes to inflammation; (iii) exploitation of host immune response to promote invasion; and (iv) the contribution of the gut microbiome to clinical disease.
Summary
Targeting these mechanisms that result in tissue injury should be a focus of future research for the development of improved preventive and therapeutic strategies for amebiasis.