Nature (2020)Cite this article
Genetic mechanisms of critical illness in Covid-19
Erola Pairo-Castineira, Sara Clohisey, […]J. Kenneth Baillie
Host-mediated lung inflammation is present,1 and drives mortality,2 in critical illness caused by Covid-19. Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development.3 Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study(GWAS) in 2244 critically ill Covid-19 patients from 208 UK intensive care units (ICUs). We identify and replicate novel genome-wide significant associations, on chr12q24.13 (rs10735079, p=1.65 × 10-8) in a gene cluster encoding antiviral restriction enzyme activators (OAS1, OAS2, OAS3), on chr19p13.2 (rs2109069, p=2.3 × 10-12) near the gene encoding tyrosine kinase 2 (TYK2), on chr19p13.3 (rs2109069, p=3.98 × 10-12) within the gene encoding dipeptidyl peptidase 9 (DPP9), and on chr21q22.1 (rs2236757, p=4.99 × 10-8) in the interferon receptor gene IFNAR2. We identify potential targets for repurposing of licensed medications: using Mendelian randomisation we found evidence in support of a causal link from low expression of IFNAR2, and high expression of TYK2, to life-threatening disease; transcriptome-wide association in lung tissue revealed that high expression of the monocyte/macrophage chemotactic receptor CCR2 is associated with severe Covid-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms, and mediators of inflammatory organ damage in Covid-19. Both mechanisms may be amenable to targeted treatment with existing drugs. Large-scale randomised clinical trials will be essential before any change to clinical practice.
Antiviral Res. 2020 Oct;182:104902. doi: 10.1016/j.antiviral.2020.104902. Epub 2020 Jul 30.
The chemokine receptor antagonist cenicriviroc inhibits the replication of SARS-CoV-2 in vitro
Mika Okamoto 1, Masaaki Toyama 1, Masanori Baba 2
Cenicriviroc (CVC) is a small-molecule chemokine receptor antagonist with highly potent and selective anti-human immunodeficiency virus type 1 (HIV-1) activity through antagonizing C-C chemokine receptor type 5 (CCR5) as a coreceptor of HIV-1. CVC also strongly antagonizes C-C chemokine receptor type 2b (CCR2b), thereby it has potent anti-inflammatory and immunomodulatory effects. CVC is currently under clinical trials in the patients for treatment of nonalcoholic steatohepatitis, in which immune cell activation and dysregulation of proinflammatory cytokines play an important role in its pathogenesis. In this study, CVC was examined for its inhibitory effect on the replication of SARS-CoV-2, the causative agent of COVID-19, in cell cultures and found to be a selective inhibitor of the virus. The 50% effective concentrations of CVC were 19.0 and 2.9 μM in the assays based on the inhibition of virus-induced cell destruction and viral RNA levels in culture supernatants of the infected cells, respectively. Interestingly, the CCR5-specific antagonist maraviroc did not show any anti-SARS-CoV-2 activity. Although the mechanism of SARS-CoV-2 inhibition by CVC remains to be elucidated, CCR2b does not seem to be its target molecule. Considering the fact that the regulation of excessive immune activation is required to treat COVID-19 patients at the late stage of the disease, CVC should be further pursued for its potential in the treatment of SARS-CoV-2 infection.
Trends Microbiol. 2003 Aug;11(8):383-91. doi: 10.1016/s0966-842x(03)00157-4.
Chemokines and viruses: friends or foes?
Surendran Mahalingam 1, Jon S Friedland, Mark T Heise, Nestor E Rulli, Jayesh Meanger, Brett A Lidbury
The chemokine-mediated movement of leukocytes from peripheral blood into tissues is essential for immunity in higher organisms. In addition, chemokines play crucial roles in controlling the development and functional aspects of leukocytes, and it is now apparent that their role is not only restricted to cell attraction. Recent in vitro and in vivo findings support the contribution of the chemokine system in the resolution of viral infections. However, the chemokine response to other viral infections can be detrimental to the host because of aberrant cellular activity. This review aims to provide insights into both sides of the chemokine spectrum, and will touch on aspects of chemokine mimicry by RNA viruses and the possible implication for disease outcome.
Blood. 2005 Oct 1; 106(7): 2366–2374.
Chemokine up-regulation in SARS-coronavirus–infected, monocyte-derived human dendritic cells
Helen K. W. Law, Chung Yan Cheung, Hoi Yee Ng, Sin Fun Sia, Yuk On Chan, Winsie Luk, John M. Nicholls, J. S. Malik Peiris, and Yu Lung Lau
Lymphopenia and increasing viral load in the first 10 days of severe acute respiratory syndrome (SARS) suggested immune evasion by SARS-coronavirus (CoV). In this study, we focused on dendritic cells (DCs) which play important roles in linking the innate and adaptive immunity. SARS-CoV was shown to infect both immature and mature human monocyte-derived DCs by electron microscopy and immunofluorescence. The detection of negative strands of SARS-CoV RNA in DCs suggested viral replication. However, no increase in viral RNA was observed. Using cytopathic assays, no increase in virus titer was detected in infected DCs and cell-culture supernatant, confirming that virus replication was incomplete. No induction of apoptosis or maturation was detected in SARS-CoV–infected DCs. The SARS-CoV–infected DCs showed low expression of antiviral cytokines (interferon α [IFN-α], IFN-β, IFN-γ, and interleukin 12p40 [IL-12p40]), moderate up-regulation of proinflammatory cytokines (tumor necrosis factor α [TNF-α] and IL-6) but significant up-regulation of inflammatory chemokines (macrophage inflammatory protein 1α [MIP-1α], regulated on activation normal T cell expressed and secreted [RANTES]), interferon-inducible protein of 10 kDa [IP-10], and monocyte chemoattractant protein 1 [MCP-1]). The lack of antiviral cytokine response against a background of intense chemokine up-regulation could represent a mechanism of immune evasion by SARS-CoV.
BMC Immunology volume 10, Article number: 35 (2009) Cite this article
Toll-like receptors, chemokine receptors and death receptor ligands responses in SARS coronavirus infected human monocyte derived dendritic cells
Helen KW Law, Chung Yan Cheung, Sin Fun Sia, Yuk On Chan, JS Malik Peiris & Yu Lung Lau
The SARS outbreak in 2003 provides a unique opportunity for the study of human responses to a novel virus. We have previously reported that dendritic cells (DCs) might be involved in the immune escape mechanisms for SARS-CoV. In this study, we focussed on the gene expression of toll-like receptors (TLRs), chemokine receptors (CCRs) and death receptor ligands in SARS-CoV infected DCs. We also compared adult and cord blood (CB) DCs to find a possible explanation for the age-dependent severity of SARS.
Our results demonstrates that SARS-CoV did not modulate TLR-1 to TLR-10 gene expression but significantly induced the expression of CCR-1, CCR-3, and CCR-5. There was also strong induction of TNF-related apoptosis-inducing ligand (TRAIL), but not Fas ligand gene expression in SARS-CoV infected DCs. Interestingly, the expressions of most genes studied were higher in CB DCs than adult DCs.
The upregulation of chemokines and CCRs may facilitate DC migration from the infection site to the lymph nodes, whereas the increase of TRAIL may induce lymphocyte apoptosis. These findings may explain the increased lung infiltrations and lymphoid depletion in SARS patients. Further explorations of the biological significance of these findings are warranted.
PLoS Pathog. 2008 Dec;4(12):e1000240. doi: 10.1371/journal.ppat.1000240. Epub 2008 Dec 12.
MyD88 is required for protection from lethal infection with a mouse-adapted SARS-CoV
Timothy Sheahan 1, Thomas E Morrison, William Funkhouser, Satoshi Uematsu, Shizou Akira, Ralph S Baric, Mark T Heise
A novel human coronavirus, SARS-CoV, emerged suddenly in 2003, causing approximately 8000 human cases and more than 700 deaths worldwide. Since most animal models fail to faithfully recapitulate the clinical course of SARS-CoV in humans, the virus and host factors that mediate disease pathogenesis remain unclear. Recently, our laboratory and others developed a recombinant mouse-adapted SARS-CoV (rMA15) that was lethal in BALB/c mice. In contrast, intranasal infection of young 10-week-old C57BL/6 mice with rMA15 results in a nonlethal infection characterized by high titer replication within the lungs, lung inflammation, destruction of lung tissue, and loss of body weight, thus providing a useful model to identify host mediators of protection. Here, we report that mice deficient in MyD88 (MyD88(-/-)), an adapter protein that mediates Toll-like receptor (TLR), IL-1R, and IL-18R signaling, are far more susceptible to rMA15 infection. The genetic absence of MyD88 resulted in enhanced pulmonary pathology and greater than 90% mortality by day 6 post-infection. MyD88(-/-) mice had significantly higher viral loads in lung tissue throughout the course of infection. Despite increased viral loads, the expression of multiple proinflammatory cytokines and chemokines within lung tissue and recruitment of inflammatory monocytes/macrophages to the lung was severely impaired in MyD88(-/-) mice compared to wild-type mice. Furthermore, mice deficient in chemokine receptors that contribute to monocyte recruitment to the lung were more susceptible to rMA15-induced disease and exhibited severe lung pathology similar to that seen in MyD88(-/-)mice. These data suggest that MyD88-mediated innate immune signaling and inflammatory cell recruitment to the lung are required for protection from lethal rMA15 infection.
J Immunol. 2004 Sep 15;173(6):4030-9. doi: 10.4049/jimmunol.173.6.4030.
Mechanisms of host defense following severe acute respiratory syndrome-coronavirus (SARS-CoV) pulmonary infection of mice
William G Glass 1, Kanta Subbarao, Brian Murphy, Philip M Murphy
We describe a model of severe acute respiratory syndrome-coronavirus (SARS-CoV) infection in C57BL/6 mice. A clinical isolate of the virus introduced intranasally replicated transiently to high levels in the lungs of these mice, with a peak on day 3 and clearance by day 9 postinfection. Viral RNA localized to bronchial and bronchiolar epithelium. Expression of mRNA for angiotensin converting enzyme 2, the SARS-CoV receptor, was detected in the lung following infection. The virus induced production in the lung of the proinflammatory chemokines CCL2, CCL3, CCL5, CXCL9, and CXCL10 with differential kinetics. The receptors for these chemokines were also detected. Most impressively, mRNA for CXCR3, the receptor for CXCL9 and CXCL10, was massively up-regulated in the lungs of SARS-CoV-infected mice. Surprisingly Th1 (and Th2) cytokines were not detectable, and there was little local accumulation of leukocytes and no obvious clinical signs of pulmonary dysfunction. Moreover, beige, CD1-/-, and RAG1-/- mice cleared the virus normally. Infection spread to the brain as it was cleared from the lung, again without leukocyte accumulation. Infected mice had a relative failure to thrive, gaining weight significantly more slowly than uninfected mice. These data indicate that C57BL/6 mice support transient nonfatal systemic infection with SARS-CoV in the lung, which is able to disseminate to brain. In this species, proinflammatory chemokines may coordinate a rapid and highly effective innate antiviral response in the lung, but NK cells and adaptive cellular immunity are not required for viral clearance.
Viral Immunol. 2007 Dec;20(4):599-608. doi: 10.1089/vim.2007.0056.
CCR1 deficiency increases susceptibility to fatal coronavirus infection of the central nervous system
Michelle J Hickey 1, Katherine S Held, Elizabeth Baum, Ji-Liang Gao, Philip M Murphy, Thomas E Lane
The role of CC chemokine receptor 1 (CCR1) in host defense and disease development was determined in a model of viral-induced neurologic disease. Intracerebral (IC) infection of mice with mouse hepatitis virus (MHV) results in an acute encephalitis followed by a chronic demyelinating disease similar in pathology to the disease multiple sclerosis (MS). No increase in mortality was observed during the acute phase of disease following MHV infection of mice lacking CCR1 (CCR1-/-) as compared to wild-type (CCR1+/+) mice. However, by 21 d post-infection, 74% of CCR1-/- mice had succumbed to death compared to only 32% mortality of CCR1+/+ mice, indicating that chemokine signaling through CCR1 significantly (p <or= 0.04) enhanced survival following IC infection with MHV. Increased mortality in CCR1-/- mice was not associated with increased viral recovery from the CNS, although CCR1 deficiency correlated with reduced T-cell accumulation within the CNS during acute, but not chronic, disease. Despite the reduction in T-cell trafficking into the CNS of CCR1-/- mice during acute disease, components of host defense remained unaltered; T-cell effector functions including cytolytic activity and proliferation and the expression of IFN-gamma within the CNS were not significantly different between CCR1+/+ and CCR1-/- infected mice. In addition, macrophage infiltration into the CNS was unaffected in MHV-infected CCR1-/- mice when compared to CCR1+/+ mice. Furthermore, assessment of neuropathology revealed no difference in the severity of demyelination between CCR1-deficient and wild-type mice. Together, these findings reveal that T-cell and macrophage trafficking are not dependent on CCR1 and highlight an important role for CCR1 signaling in promoting survival during chronic MHV infection.