Reply to “Statins may decrease the Fatality Rate of MERS Infection”

Since the emergence of Middle East respiratory syndrome coronavirus (MERS-CoV) on the Arabian Peninsula in 2012, there has been a steady stream of MERS cases geographically focused in the Middle East, indicating that either zoonotic transmission from camel to human or person-to-person transmission likely takes place on a frequent basis (1). As reaffirmed by the recent MERS outbreak in South Korea, highly pathogenic coronaviruses are capable of causing epidemics affecting hundreds of individuals as a result of sustained person-to-person transmission in nosocomial settings that can be linked to a single traveler who became an index patient (2). Currently, the best public health strategy to circumvent sustained coronavirus transmission in an outbreak situation is to quarantine individuals who have a history of contact with confirmed cases of MERS. In the most recent outbreak in South Korea, this led to the isolation and monitoring of more than 16,000 individuals, a feat that may not be economically or logistically feasible in future outbreaks (2). Due to the diversity and presence of prepandemic zoonotic coronaviruses in bat populations, we may expect the continual reemergence of highly pathogenic coronaviruses related to MERS-CoV, SARS-CoV (severe acute respiratory syndrome coronavirus), or other CoV strains to be a future risk to global public health (3, 4). There is clearly a need for coronavirus-specific medical countermeasure strategies against these respiratory pathogens, as studies indicate that general antiviral medications like interferon and ribavirin are ineffective in MERS or SARS patients (5, 6)

Toll-Like Receptor 3 Signaling via TRIF Contributes to a Protective Innate Immune Response to Severe Acute Respiratory Syndrome Coronavirus Infection

ABSTRACTToll-like receptors (TLRs) are sensors that recognize molecular patterns from viruses, bacteria, and fungi to initiate innate immune responses to invading pathogens. The emergence of highly pathogenic coronaviruses severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) is a concern for global public health, as there is a lack of efficacious vaccine platforms and antiviral therapeutic strategies. Previously, it was shown that MyD88, an adaptor protein necessary for signaling by multiple TLRs, is a required component of the innate immune response to mouse-adapted SARS-CoV infection in vivo. Here, we demonstrate that TLR3−/−, TLR4−/−, and TRAM−/− mice are more susceptible to SARS-CoV than wild-type mice but experience only transient weight loss with no mortality in response to infection. In contrast, mice deficient in the TLR3/TLR4 adaptor TRIF are highly susceptible to SARS-CoV infection, showing increased weight loss, mortality, reduced lung function, increased lung pathology, and higher viral titers. Distinct alterations in inflammation were present in TRIF−/− mice infected with SARS-CoV, including excess infiltration of neutrophils and inflammatory cell types that correlate with increased pathology of other known causes of acute respiratory distress syndrome (ARDS), including influenza virus infections. Aberrant proinflammatory cytokine, chemokine, and interferon-stimulated gene (ISG) signaling programs were also noted following infection of TRIF−/− mice that were similar to those seen in human patients with poor disease outcome following SARS-CoV or MERS-CoV infection. These findings highlight the importance of TLR adaptor signaling in generating a balanced protective innate immune response to highly pathogenic coronavirus infections.IMPORTANCEToll-like receptors are a family of sensor proteins that enable the immune system to differentiate between “self” and “non-self.” Agonists and antagonists of TLRs have been proposed to have utility as vaccine adjuvants or antiviral compounds. In the last 15 years, the emergence of highly pathogenic coronaviruses SARS-CoV and MERS-CoV has caused significant disease accompanied by high mortality rates in human populations, but no approved therapeutic treatments or vaccines currently exist. Here, we demonstrate that TLR signaling through the TRIF adaptor protein protects mice from lethal SARS-CoV disease. Our findings indicate that a balanced immune response operating through both TRIF-driven and MyD88-driven pathways likely provides the most effective host cell intrinsic antiviral defense responses to severe SARS-CoV disease, while removal of either branch of TLR signaling causes lethal SARS-CoV disease in our mouse model. These data should inform the design and use of TLR agonists and antagonists in coronavirus-specific vaccine and antiviral strategies

Allelic Variation in the Toll-Like Receptor Adaptor Protein

Host genetic variation is known to contribute to differential pathogenesis following infection. Mouse models allow direct assessment of host genetic factors responsible for susceptibility to Severe Acute Respiratory Syndrome coronavirus (SARS-CoV). Based on an assessment of early stage lines from the Collaborative Cross mouse multi-parent population, we identified two lines showing highly divergent susceptibilities to SARS-CoV: the resistant CC003/Unc and the susceptible CC053/Unc. We generated 264 F2 mice between these strains, and infected them with SARS-CoV. Weight loss, pulmonary hemorrhage, and viral load were all highly correlated disease phenotypes. We identified a quantitative trait locus of major effect on chromosome 18 (27.1-58.6 Mb) which affected weight loss, viral titer and hemorrhage. Additionally, each of these three phenotypes had distinct quantitative trait loci [Chr 9 (weight loss), Chrs 7 and 12 (virus titer), and Chr 15 (hemorrhage)]. We identified Ticam2 , an adaptor protein in the TLR signaling pathways, as a candidate driving differential disease at the Chr 18 locus. Ticam2 -/- mice were highly susceptible to SARS-CoV infection, exhibiting increased weight loss and more pulmonary hemorrhage than control mice. These results indicate a critical role for Ticam2 in SARS-CoV disease, and highlight the importance of host genetic variation in disease responses

Allelic variation in mouse Ticam2 contributes to SARS-CoV pathogenesis

Genotype calls from the MUGA array for an F2 cross between the mouse strains CC003/Unc and CC053/Unc. The results of this F2 cross are in press at G3 Gralinski, L. E., V. D. Menachery, A. P. Morgan, A. Totura, A. Beall et al., 2017 Allelic variation in mouse Ticam2 contributes to SARS-CoV pathogenesis. G3 7: xx-xx

The immuno-oncological challenge of COVID-19

International audienceCoronavirus disease 2019 (COVID-19) and its causative virus, SARS-CoV-2, pose considerable challenges for the management of oncology patients. COVID-19 presents as a particularly severe respiratory and systemic infection in aging and immunosuppressed individuals, including patients with cancer. Moreover, severe COVID-19 is linked to an inflammatory burst and lymphopenia, which may aggravate cancer prognosis. Here we discuss why those with cancer are at higher risk of severe COVID-19, describe immune responses that confer protective or adverse reactions to this disease and indicate which antineoplastic therapies may either increase COVID-19 vulnerability or have a dual therapeutic effect on cancer and COVID-19. Zitvogel and colleagues discuss the interplay between cancer and COVID-19 with respect to patient risk and prognosis, immune responses and potential therapies