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.

Interferons and viruses: an interplay between induction, signalling, antiviral responses and virus countermeasures.

Immunology of COVID-19: Current State of the Science.

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.

/pdf/macrophages-master-regulators-of-inflammation-and-fibrosis-3wg8gcla6z.pdf

Macrophages: master regulators of inflammation and fibrosis.

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.

COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options.

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.

Targeting the NLRP3 inflammasome in inflammatory diseases

Gene Profiles in Drug Design

https://doi.org/10.1016/j.vaccine.2023.04.010

Monkeypox (Mpox) requires continued surveillance, vaccines, therapeutics and mitigating strategies

Weiqiang Chen, Suan-Sin Foo, Adam Taylor, Aleksei Lulla, Andres Merits, Linda Hueston, Mark R. Forwood, Nicole C. Walsh, Natalie A. Sims, Lara J. Herrero, Suresh Mahalingam Institute for Glycomics, Griffith University, Gold Coast, QLD, Australia; Institute of Technology, University of Tartu, Tartu, Estonia; Arbovirus Emerging Diseases Unit, Centre for Infectious Diseases and Microbiology Laboratory Services, Westmead Hospital, Westmead, NSW, Australia; School of Medical Science and Griffith Health Institute, Griffith University, Gold Coast, QLD, Australia; St. Vincent’s Institute of Medical Research and Department of Medicine, St. Vincent’s Hospital, The University of Melbourne, Melbourne, VIC, Australia

Correction for Chen et al., Bindarit, an Inhibitor of Monocyte Chemotactic Protein Synthesis, Protects against Bone Loss Induced by Chikungunya Virus Infection

There is increasing evidence to suggest that viruses have aetiological roles in the idiopathic inflammatory myopathies. Arthrogenic alphaviruses (such as chikungunya virus, Ross River virus and sindbis virus) are known to cause outbreaks of polyarthritis worldwide. The clinical presentation of alphavirus infection includes fever, rash, arthralgia, and arthritis, however, one of the most predominant features of alphaviral disease are symptoms of myalgia with corresponding myositis. The recent outbreaks of chikungunya virus in several countries surrounding the Indian Ocean has seen millions of people affected, with case reports indicating a high incidence of myalgia and skeletal muscle involvement in the aetiology of this disease. The mechanisms of how alphaviruses cause musculoskeletal disease are slowly being unraveled with evidence to suggest that the viral induced inflammation can result in damage to the skeletal muscle tissues, possibly explaining the symptoms of myalgia. In recent years, the use of small animal models for alphavirus-induced myositis has furthered our understanding of the idiopathic inflammatory myopathies caused by these viruses. This chapter will discuss the role of alphaviruses as an often-overlooked cause of myositis, including how small animal models are being used to dissect the pathobiology of disease and identify potential drug candidates to ameliorate disease.

/pdf/arthrogenic-alphaviruses-and-inflammatory-myopathies-4u35mjfudy.pdf

Arthrogenic Alphaviruses and Inflammatory Myopathies

The majority of medical advances have been made using animals. Studies using mouse models of chikungunya-induced disease have proven invaluable for dissecting the intricate nature of the immune response to this viral infection and identifying potential targets for the development of treatment strategies. Herein we describe the common mouse models used to research the pathobiology of chikungunya virus infection to date.

Suresh Mahalingam

Papers

Gene Profiles in Drug Design

Monkeypox (Mpox) requires continued surveillance, vaccines, therapeutics and mitigating strategies

Correction for Chen et al., Bindarit, an Inhibitor of Monocyte Chemotactic Protein Synthesis, Protects against Bone Loss Induced by Chikungunya Virus Infection

Arthrogenic Alphaviruses and Inflammatory Myopathies

Mouse Models of Chikungunya Virus.