The human complement system is an important part of the innate immune system. Its effector pathwa... more The human complement system is an important part of the innate immune system. Its effector pathways largely mediate virus neutralization. Vesicular stomatitis virus (VSV) activates the classical pathway of the complement, leading to virus neutralization by lysis. Two host-derived membrane-associated regulators of complement activation (RCA), CD55 and CD46, which are incorporated into the VSV envelope during egress, confer protection by delaying/resisting complement-mediated neutralization. We showed previously that CD55 is more effective than CD46 in the inhibition of neutralization. In this study, we identified that, at the protein level, VSV infection resulted in the down-regulation of CD46 but not CD55. The mRNA of both the RCAs was significantly down-regulated by VSV, but it was delayed in the case of CD55. The immunoblot analysis of the levels of RCAs in the progeny virion harvested at three specific time intervals, points to an equal ratio of its distribution relative to viral...
Chandipura virus (CHPV) is an emerging human pathogen of great clinical significance. In this stu... more Chandipura virus (CHPV) is an emerging human pathogen of great clinical significance. In this study, we have investigated the susceptibility pattern of both normal and cancer cell lines of human origin to wild-type (wt) CHPV in order to explore the possibility of developing CHPV as an oncolytic vector (OV). Marked cytopathic effect along with enhanced virus output was observed in cancer cell lines (HeLa, A549, U-138, PC-3, and HepG2) in comparison to normal human adult dermal fibroblast (HADF) cells. At an MOI of 0.1, cancer cell lines were differentially susceptible to CHPV, with cells like HeLa and U-138 having pronounced cell death, while the PC-3 were comparatively resistant. All cell lines used in the study except U-138 restricted CHPV infection to varying degrees with IFN-β pre-treatment and supplementation of interferon (IFN) could neither activate the IFN signaling pathway in U-138 cells. Finally, U-138 tumor xenografts established in non-obese diabetic severe combined immunodeficiency (NOD/SCID) mice showed significant delay in tumor growth in the CHPV-challenged animals. Thus, targeted cytopathic effect in cancer cells at a very low dose with restricted replication in normal cells offers a rationale to exploit CHPV as an oncolytic vector in the future.
Chikungunya virus is a vector-borne pathogen of global significance. The morbidity associated wit... more Chikungunya virus is a vector-borne pathogen of global significance. The morbidity associated with chikungunya virus (CHIKV) infection, neurovirulence and adaptability to Aedes albopictus , necessitates a deeper understanding of the interaction of CHIKV with the host immune system. Here, we demonstrate that CHIKV is resistant to neutralization by one of the potent barriers of the innate immune arm, the complement system. Chikungunya virus showed marked resistance to complement despite activation and deposition of complement proteins. Interestingly the C3 component associated with the virion was found to be inactive C3b (iC3b), a key factor implicated in the pathogenesis and disease severity in the mouse model of Ross River virus infection. CHIKV also had an associated unique factor I-like activity that mediated the inactivation of C3b into iC3b. We have unraveled a smart strategy adopted by CHIKV to limit complement which has serious implications in viral dissemination, pathogenesis...
Chandipura virus is a clinically important human pathogen of the Indian subcontinent. The rapidit... more Chandipura virus is a clinically important human pathogen of the Indian subcontinent. The rapidity of death associated with CHPV infection in addition to the absence of an effective vaccine or therapeutics results in poor clinical prognosis. The biology of the virus and its interaction with the host immune system, including the complement system, are understudied. Our investigation reveals the susceptibility of CHPV to fluid phase complement and also dissects the pathway involved and the mechanism of virus neutralization. Direct binding of C1q, an important upstream component of the classical pathway of complement to CHPV, and the strong dependency on C1q for virus neutralization highlight the significance of identifying such interactions to better understand CHPV pathogenesis and devise strategies to target this deadly pathogen.
Cholera, caused by the Gram-negative bacterium Vibrio cholerae, remains a major problem in develo... more Cholera, caused by the Gram-negative bacterium Vibrio cholerae, remains a major problem in developing countries. Although the disease can be managed by oral rehydration therapy, antibiotics are widely used nowadays to treat the disease. However, chemoprophylaxis has been proven to have no effect on the spread of the disease, but acts as a major driver for antimicrobial resistance (AMR). V. cholerae has evolved different ways to combat antibiotics used against them. This review comprehends the different molecular mechanisms of antibiotic resistance in V. cholerae, gaps in the development of new antibiotics, and the alternative strategies that can be used to treat the disease. The review advocates the use of antivirulence compounds rather than antibacterial compounds as a strategy to limit the increasing AMR. Also, the review expounds the role of community in preventing the diseases and tackling the global burden of AMR.
Probiotics are live microorganisms that, when administered in adequate amounts, confer a health b... more Probiotics are live microorganisms that, when administered in adequate amounts, confer a health benefit on the host, with respect to metabolism, immune function, and nutrition. Any perturbation of these beneficial microbes leads to gut dysbiosis, which triggers the development of various disorders in the gastrointestinal system. Probiotics play a key role in resolving the dysbiosis posed by external factors such as antibiotics, other substances, or interventions. Supplementing probiotics with antibiotics is favorable in reducing the harmful effects of antibiotics on gut flora. These microbes also possess specific intrinsic drug resistance mechanisms that aid their survival in the internal environment. According to US Food and Drug Administration reports, species belonging to Lactobacillus and Bifidobacterium genera are the most common probiotics consumed by humans through commercial products. However, various studies have reported the tendency of microbes to acquire specific drug resistance, in recent years, through various mechanisms. The reports on transferable resistance among probiotics are of major concern, of which minimal information is available to date. The aim of this review was to describe the pros and cons of drug resistance among these beneficial microorganisms with emphasis on the recommended selection criteria for specific probiotics, devoid of transferable drug resistance genes, suitable for human consumption.
Many enveloped RNA viruses recruit host cell proteins during assembly as a mechanism to limit ant... more Many enveloped RNA viruses recruit host cell proteins during assembly as a mechanism to limit antiviral effects of complement. Using viruses which incorporated CD46 alone, CD55 alone or both CD46 and CD55, we addressed the role of these two host cell regulators in limiting complement-mediated neutralization of Parainfluenza virus 5 (PIV5). PIV5 incorporated functional forms of both CD55 and CD46 into virions. PIV5 containing CD55 was highly resistant to complement-mediated neutralization, whereas CD46-containing PIV5 was as sensitive to neutralization as virus lacking both regulators. PIV5 infected cells had increased levels of cell surface CD55, which was further upregulated by exogenous treatment with tumor necrosis factor alpha. PIV5 derived from cells with higher CD55 levels was more resistant to complement-mediated neutralization in vitro than virus from control cells. We propose a role for virus induction of host cell complement inhibitors in defining virus growth and tissue t...
Complement is an innate immune system that most animal viruses must face during natural infection... more Complement is an innate immune system that most animal viruses must face during natural infections. Given that replication and dissemination of the highly pathogenic Nipah virus (NiV) include exposure to environments rich in complement factors, we tested the in vitro sensitivity of NiV to complement-mediated neutralization. Here we show that NiV was completely resistant to in vitro neutralization by normal human serum (NHS). Treatment of purified NiV with NHS activated complement pathways, but there was very little C3 deposition on virus particles. In in vitro reconstitution experiments, NiV particles provided time- and dose-dependent factor I-like protease activity capable of cleaving C3b into inactive C3b (iC3b). NiV-dependent inactivation of C3b only occurred with the cofactors factor H and soluble CR1 but not with CD46. Purified NiV particles did not support C4b cleavage. Electron microscopy of purified NiV particles showed immunogold labeling with anti-factor I antibodies. Our ...
The human complement system is an important part of the innate immune system. Its effector pathwa... more The human complement system is an important part of the innate immune system. Its effector pathways largely mediate virus neutralization. Vesicular stomatitis virus (VSV) activates the classical pathway of the complement, leading to virus neutralization by lysis. Two host-derived membrane-associated regulators of complement activation (RCA), CD55 and CD46, which are incorporated into the VSV envelope during egress, confer protection by delaying/resisting complement-mediated neutralization. We showed previously that CD55 is more effective than CD46 in the inhibition of neutralization. In this study, we identified that, at the protein level, VSV infection resulted in the down-regulation of CD46 but not CD55. The mRNA of both the RCAs was significantly down-regulated by VSV, but it was delayed in the case of CD55. The immunoblot analysis of the levels of RCAs in the progeny virion harvested at three specific time intervals, points to an equal ratio of its distribution relative to viral...
Chandipura virus (CHPV) is an emerging human pathogen of great clinical significance. In this stu... more Chandipura virus (CHPV) is an emerging human pathogen of great clinical significance. In this study, we have investigated the susceptibility pattern of both normal and cancer cell lines of human origin to wild-type (wt) CHPV in order to explore the possibility of developing CHPV as an oncolytic vector (OV). Marked cytopathic effect along with enhanced virus output was observed in cancer cell lines (HeLa, A549, U-138, PC-3, and HepG2) in comparison to normal human adult dermal fibroblast (HADF) cells. At an MOI of 0.1, cancer cell lines were differentially susceptible to CHPV, with cells like HeLa and U-138 having pronounced cell death, while the PC-3 were comparatively resistant. All cell lines used in the study except U-138 restricted CHPV infection to varying degrees with IFN-β pre-treatment and supplementation of interferon (IFN) could neither activate the IFN signaling pathway in U-138 cells. Finally, U-138 tumor xenografts established in non-obese diabetic severe combined immunodeficiency (NOD/SCID) mice showed significant delay in tumor growth in the CHPV-challenged animals. Thus, targeted cytopathic effect in cancer cells at a very low dose with restricted replication in normal cells offers a rationale to exploit CHPV as an oncolytic vector in the future.
Chikungunya virus is a vector-borne pathogen of global significance. The morbidity associated wit... more Chikungunya virus is a vector-borne pathogen of global significance. The morbidity associated with chikungunya virus (CHIKV) infection, neurovirulence and adaptability to Aedes albopictus , necessitates a deeper understanding of the interaction of CHIKV with the host immune system. Here, we demonstrate that CHIKV is resistant to neutralization by one of the potent barriers of the innate immune arm, the complement system. Chikungunya virus showed marked resistance to complement despite activation and deposition of complement proteins. Interestingly the C3 component associated with the virion was found to be inactive C3b (iC3b), a key factor implicated in the pathogenesis and disease severity in the mouse model of Ross River virus infection. CHIKV also had an associated unique factor I-like activity that mediated the inactivation of C3b into iC3b. We have unraveled a smart strategy adopted by CHIKV to limit complement which has serious implications in viral dissemination, pathogenesis...
Chandipura virus is a clinically important human pathogen of the Indian subcontinent. The rapidit... more Chandipura virus is a clinically important human pathogen of the Indian subcontinent. The rapidity of death associated with CHPV infection in addition to the absence of an effective vaccine or therapeutics results in poor clinical prognosis. The biology of the virus and its interaction with the host immune system, including the complement system, are understudied. Our investigation reveals the susceptibility of CHPV to fluid phase complement and also dissects the pathway involved and the mechanism of virus neutralization. Direct binding of C1q, an important upstream component of the classical pathway of complement to CHPV, and the strong dependency on C1q for virus neutralization highlight the significance of identifying such interactions to better understand CHPV pathogenesis and devise strategies to target this deadly pathogen.
Cholera, caused by the Gram-negative bacterium Vibrio cholerae, remains a major problem in develo... more Cholera, caused by the Gram-negative bacterium Vibrio cholerae, remains a major problem in developing countries. Although the disease can be managed by oral rehydration therapy, antibiotics are widely used nowadays to treat the disease. However, chemoprophylaxis has been proven to have no effect on the spread of the disease, but acts as a major driver for antimicrobial resistance (AMR). V. cholerae has evolved different ways to combat antibiotics used against them. This review comprehends the different molecular mechanisms of antibiotic resistance in V. cholerae, gaps in the development of new antibiotics, and the alternative strategies that can be used to treat the disease. The review advocates the use of antivirulence compounds rather than antibacterial compounds as a strategy to limit the increasing AMR. Also, the review expounds the role of community in preventing the diseases and tackling the global burden of AMR.
Probiotics are live microorganisms that, when administered in adequate amounts, confer a health b... more Probiotics are live microorganisms that, when administered in adequate amounts, confer a health benefit on the host, with respect to metabolism, immune function, and nutrition. Any perturbation of these beneficial microbes leads to gut dysbiosis, which triggers the development of various disorders in the gastrointestinal system. Probiotics play a key role in resolving the dysbiosis posed by external factors such as antibiotics, other substances, or interventions. Supplementing probiotics with antibiotics is favorable in reducing the harmful effects of antibiotics on gut flora. These microbes also possess specific intrinsic drug resistance mechanisms that aid their survival in the internal environment. According to US Food and Drug Administration reports, species belonging to Lactobacillus and Bifidobacterium genera are the most common probiotics consumed by humans through commercial products. However, various studies have reported the tendency of microbes to acquire specific drug resistance, in recent years, through various mechanisms. The reports on transferable resistance among probiotics are of major concern, of which minimal information is available to date. The aim of this review was to describe the pros and cons of drug resistance among these beneficial microorganisms with emphasis on the recommended selection criteria for specific probiotics, devoid of transferable drug resistance genes, suitable for human consumption.
Many enveloped RNA viruses recruit host cell proteins during assembly as a mechanism to limit ant... more Many enveloped RNA viruses recruit host cell proteins during assembly as a mechanism to limit antiviral effects of complement. Using viruses which incorporated CD46 alone, CD55 alone or both CD46 and CD55, we addressed the role of these two host cell regulators in limiting complement-mediated neutralization of Parainfluenza virus 5 (PIV5). PIV5 incorporated functional forms of both CD55 and CD46 into virions. PIV5 containing CD55 was highly resistant to complement-mediated neutralization, whereas CD46-containing PIV5 was as sensitive to neutralization as virus lacking both regulators. PIV5 infected cells had increased levels of cell surface CD55, which was further upregulated by exogenous treatment with tumor necrosis factor alpha. PIV5 derived from cells with higher CD55 levels was more resistant to complement-mediated neutralization in vitro than virus from control cells. We propose a role for virus induction of host cell complement inhibitors in defining virus growth and tissue t...
Complement is an innate immune system that most animal viruses must face during natural infection... more Complement is an innate immune system that most animal viruses must face during natural infections. Given that replication and dissemination of the highly pathogenic Nipah virus (NiV) include exposure to environments rich in complement factors, we tested the in vitro sensitivity of NiV to complement-mediated neutralization. Here we show that NiV was completely resistant to in vitro neutralization by normal human serum (NHS). Treatment of purified NiV with NHS activated complement pathways, but there was very little C3 deposition on virus particles. In in vitro reconstitution experiments, NiV particles provided time- and dose-dependent factor I-like protease activity capable of cleaving C3b into inactive C3b (iC3b). NiV-dependent inactivation of C3b only occurred with the cofactors factor H and soluble CR1 but not with CD46. Purified NiV particles did not support C4b cleavage. Electron microscopy of purified NiV particles showed immunogold labeling with anti-factor I antibodies. Our ...
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