Author
Suresh Mahalingam
Other affiliations: Indian Institute of Technology Madras, RMIT University, Applied Science Private University ...read more
Bio: Suresh Mahalingam is an academic researcher from Griffith University. The author has contributed to research in topics: Virus & Chikungunya. The author has an hindex of 37, co-authored 116 publications receiving 4683 citations. Previous affiliations of Suresh Mahalingam include Indian Institute of Technology Madras & RMIT University.
Topics: Virus, Chikungunya, Alphavirus, Arthritis, Ross River virus
Papers published on a yearly basis
Papers
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TL;DR: This Seminar focuses on the re-emergence of chikungunya, the clinical manifestations, pathogenesis of virus-induced arthralgia, diagnostic techniques, and various treatment modalities.
523 citations
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TL;DR: Insights into intracellular mechanisms and implications of enhanced pathogenesis after ligation of macrophage Fcγ receptors by infectious immune complexes are reviewed.
Abstract: Summary A wide range of microorganisms can replicate in macrophages, and cell entry of these pathogens via non-neutralising IgG antibody complexes can result in increased intracellular infection through idiosyncratic Fcγ-receptor signalling. The activation of Fcγ receptors usually leads to phagocytosis. Paradoxically, the ligation of monocyte or macrophage Fcγ receptors by IgG immune complexes, rather than aiding host defences, can suppress innate immunity, increase production of interleukin 10, and bias T-helper-1 (Th1) responses to Th2 responses, leading to increased infectious output by infected cells. This intrinsic antibody-dependent enhancement (ADE) of infection modulates the severity of diseases as disparate as dengue haemorrhagic fever and leishmaniasis. Intrinsic ADE is distinct from extrinsic ADE, whereby complexes of infectious agents with non-neutralising antibodies lead to an increased number of infected cells. Intrinsic ADE might be involved in many protozoan, bacterial, and viral infections. We review insights into intracellular mechanisms and implications of enhanced pathogenesis after ligation of macrophage Fcγ receptors by infectious immune complexes.
364 citations
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TL;DR: An update on chikungunya virus with regard to its epidemiology, molecular virology, virus-host interactions, immunological responses, animal models, and potential antiviral therapies and vaccines is provided.
Abstract: Re-emergence of chikungunya virus, a mosquito-transmitted pathogen, is of serious public health concern. In the past 15 years, after decades of infrequent, sporadic outbreaks, the virus has caused major epidemic outbreaks in Africa, Asia, the Indian Ocean, and more recently the Caribbean and the Americas. Chikungunya virus is mainly transmitted by Aedes aegypti mosquitoes in tropical and subtropical regions, but the potential exists for further spread because of genetic adaptation of the virus to Aedes albopictus, a species that thrives in temperate regions. Chikungunya virus represents a substantial health burden to affected populations, with symptoms that include severe joint and muscle pain, rashes, and fever, as well as prolonged periods of disability in some patients. The inflammatory response coincides with raised levels of immune mediators and infiltration of immune cells into infected joints and surrounding tissues. Animal models have provided insights into disease pathology and immune responses. Although host innate and adaptive responses have a role in viral clearance and protection, they can also contribute to virus-induced immune pathology. Understanding the mechanisms of host immune responses is essential for the development of treatments and vaccines. Inhibitory compounds targeting key inflammatory pathways, as well as attenuated virus vaccines, have shown some success in animal models, including an attenuated vaccine strain based on an isolate from La Reunion incorporating an internal ribosome entry sequence that prevents the virus from infecting mosquitoes and a vaccine based on virus-like particles expressing envelope proteins. However, immune correlates of protection, as well as the safety of prophylactic and therapeutic candidates, are important to consider for their application in chikungunya infections. In this Review, we provide an update on chikungunya virus with regard to its epidemiology, molecular virology, virus-host interactions, immunological responses, animal models, and potential antiviral therapies and vaccines.
289 citations
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TL;DR: It is demonstrated that eosinophils can protect against RSV in vivo, as they promote virus clearance and may thus limit virus-induced lung dysfunction.
249 citations
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TL;DR: In vitro studies confirm in vitro studies confirming ADE as a feature of infection for a growing number of viruses and challenges remain in understanding the multilayered molecular mechanisms of ADE and its effect on viral pathogenesis.
Abstract: Sensitization of the humoral immune response to invading viruses and production of antiviral antibodies forms part of the host antiviral repertoire. Paradoxically, for a number of viral pathogens, under certain conditions, antibodies provide an attractive means of enhanced virus entry and replication in a number of cell types. Known as antibody-dependent enhancement (ADE) of infection, the phenomenon occurs when virus-antibody immunocomplexes interact with cells bearing complement or Fc receptors, promoting internalization of the virus and increasing infection. Frequently associated with exacerbation of viral disease, ADE of infection presents a major obstacle to the prevention of viral disease by vaccination and is thought to be partly responsible for the adverse effects of novel antiviral therapeutics such as intravenous immunoglobulins. There is a growing body of work examining the intracellular signaling pathways and epitopes responsible for mediating ADE, with a view to aiding rational design of antiviral strategies. With in vitro studies also confirming ADE as a feature of infection for a growing number of viruses, challenges remain in understanding the multilayered molecular mechanisms of ADE and its effect on viral pathogenesis.
205 citations
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TL;DR: Applied aspects that arise from an increase in knowledge in this area are described, including vaccine design and manufacture, the development of novel antiviral drugs and the use of IFN-sensitive oncolytic viruses in the treatment of cancer.
Abstract: The interferon (IFN) system is an extremely powerful antiviral response that is capable of controlling most, if not all, virus infections in the absence of adaptive immunity. However, viruses can still replicate and cause disease in vivo, because they have some strategy for at least partially circumventing the IFN response. We reviewed this topic in 2000 [Goodbourn, S., Didcock, L. & Randall, R. E. (2000). J Gen Virol 81, 2341-2364] but, since then, a great deal has been discovered about the molecular mechanisms of the IFN response and how different viruses circumvent it. This information is of fundamental interest, but may also have practical application in the design and manufacture of attenuated virus vaccines and the development of novel antiviral drugs. In the first part of this review, we describe how viruses activate the IFN system, how IFNs induce transcription of their target genes and the mechanism of action of IFN-induced proteins with antiviral action. In the second part, we describe how viruses circumvent the IFN response. Here, we reflect upon possible consequences for both the virus and host of the different strategies that viruses have evolved and discuss whether certain viruses have exploited the IFN response to modulate their life cycle (e.g. to establish and maintain persistent/latent infections), whether perturbation of the IFN response by persistent infections can lead to chronic disease, and the importance of the IFN system as a species barrier to virus infections. Lastly, we briefly describe applied aspects that arise from an increase in our knowledge in this area, including vaccine design and manufacture, the development of novel antiviral drugs and the use of IFN-sensitive oncolytic viruses in the treatment of cancer.
1,564 citations
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TL;DR: The current state of knowledge of innate and adaptive immune responses elicited by SARS-CoV-2 infection and the immunological pathways that likely contribute to disease severity and death are summarized.
1,350 citations
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TL;DR: Although collagen-secreting myofibroblasts once were thought of as the master "producers" of fibrosis, this review will illustrate how macrophages function as the Master "regulators" of Fibrosis.
Abstract: Macrophages are found in close proximity with collagen-producing myofibroblasts and indisputably play a key role in fibrosis. They produce profibrotic mediators that directly activate fibroblasts, including transforming growth factor-β1 and platelet-derived growth factor, and control extracellular matrix turnover by regulating the balance of various matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases. Macrophages also regulate fibrogenesis by secreting chemokines that recruit fibroblasts and other inflammatory cells. With their potential to act in both a pro- and antifibrotic capacity, as well as their ability to regulate the activation of resident and recruited myofibroblasts, macrophages and the factors they express are integrated into all stages of the fibrotic process. These various, and sometimes opposing, functions may be performed by distinct macrophage subpopulations, the identification of which is a growing focus of fibrosis research. Although collagen-secreting myofibroblasts once were thought of as the master “producers” of fibrosis, this review will illustrate how macrophages function as the master “regulators” of fibrosis.
1,129 citations
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Jagiellonian University1, University of Glasgow2, Queen Mary University of London3, Vanderbilt University Medical Center4, University of Manchester5, University of Naples Federico II6, University of Roehampton7, University of Texas at Austin8, Jagiellonian University Medical College9, Humboldt University of Berlin10, Huazhong University of Science and Technology11, Catholic University of the Sacred Heart12
TL;DR: While ACE2 is essential for viral invasion, there is no evidence that ACE inhibitors or angiotensin receptor blockers (ARBs) worsen prognosis, Hence, patients should not discontinue their use.
Abstract: The novel coronavirus disease (COVID-19) outbreak, caused by SARS-CoV-2, represents the greatest medical challenge in decades. We provide a comprehensive review of the clinical course of COVID-19, its comorbidities, and mechanistic considerations for future therapies. While COVID-19 primarily affects the lungs, causing interstitial pneumonitis and severe acute respiratory distress syndrome (ARDS), it also affects multiple organs, particularly the cardiovascular system. Risk of severe infection and mortality increase with advancing age and male sex. Mortality is increased by comorbidities: cardiovascular disease, hypertension, diabetes, chronic pulmonary disease, and cancer. The most common complications include arrhythmia (atrial fibrillation, ventricular tachyarrhythmia, and ventricular fibrillation), cardiac injury [elevated highly sensitive troponin I (hs-cTnI) and creatine kinase (CK) levels], fulminant myocarditis, heart failure, pulmonary embolism, and disseminated intravascular coagulation (DIC). Mechanistically, SARS-CoV-2, following proteolytic cleavage of its S protein by a serine protease, binds to the transmembrane angiotensin-converting enzyme 2 (ACE2) -a homologue of ACE-to enter type 2 pneumocytes, macrophages, perivascular pericytes, and cardiomyocytes. This may lead to myocardial dysfunction and damage, endothelial dysfunction, microvascular dysfunction, plaque instability, and myocardial infarction (MI). While ACE2 is essential for viral invasion, there is no evidence that ACE inhibitors or angiotensin receptor blockers (ARBs) worsen prognosis. Hence, patients should not discontinue their use. Moreover, renin-angiotensin-aldosterone system (RAAS) inhibitors might be beneficial in COVID-19. Initial immune and inflammatory responses induce a severe cytokine storm [interleukin (IL)-6, IL-7, IL-22, IL-17, etc.] during the rapid progression phase of COVID-19. Early evaluation and continued monitoring of cardiac damage (cTnI and NT-proBNP) and coagulation (D-dimer) after hospitalization may identify patients with cardiac injury and predict COVID-19 complications. Preventive measures (social distancing and social isolation) also increase cardiovascular risk. Cardiovascular considerations of therapies currently used, including remdesivir, chloroquine, hydroxychloroquine, tocilizumab, ribavirin, interferons, and lopinavir/ritonavir, as well as experimental therapies, such as human recombinant ACE2 (rhACE2), are discussed.
1,060 citations
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TL;DR: Recent advances in the understanding of NLRP3 activation and regulation are reviewed, the evolving landscape ofNLRP3 modulators are highlighted and opportunities for pharmacologically targeting NL RP3 with novel small molecules are discussed.
Abstract: Danger signals are a hallmark of many common inflammatory diseases, and these stimuli can function to activate the cytosolic innate immune signalling receptor NLRP3 (NOD-, LRR- and pyrin domain-containing 3). Once activated, NLRP3 nucleates the assembly of an inflammasome, leading to caspase 1-mediated proteolytic activation of the interleukin-1β (IL-1β) family of cytokines, and induces an inflammatory, pyroptotic cell death. Pharmacological inhibition of NLRP3 activation results in potent therapeutic effects in a wide variety of rodent models of inflammatory diseases, effects that are mirrored by genetic ablation of NLRP3. Although these findings highlight the potential of NLRP3 as a drug target, an understanding of NLRP3 structure and activation mechanisms is incomplete, which has hampered the discovery and development of novel therapeutics against this target. Here, we review recent advances in our understanding of NLRP3 activation and regulation, highlight the evolving landscape of NLRP3 modulators and discuss opportunities for pharmacologically targeting NLRP3 with novel small molecules.
1,018 citations