Document text
Principal Investigator: Daniel Barber
Organization: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
Fiscal Year: 2024
Award: $397,520
Funding agency: National Institute of Allergy and Infectious Diseases
SARS-CoV-2 infection has a spectrum of clinical disease outcomes, ranging from asymptomatic to fatal. The severity of COVID-19 is largely determined by the degree of virus-induced damage and immune-mediated pathology. However, the factors that prevent or promote pulmonary inflammation during SARS-CoV-2 infection are not well understood. Rhesus macaques experimentally infected with SARS-CoV-2 develop mild signs of disease and clear most of the virus within a couple weeks. Accordingly, this species is a useful model for examining the mechanisms of effective viral control and well-controlled inflammatory response that occurs in most individuals with SARS-CoV-2 infection. Here we use rhesus macaques to examine the roles of prototypic pro- and anti-inflammatory cytokines IFNγ and IL-10, respectively, in host resistance to SARS-CoV-2 infection and the development of COVID-19 disease.
Type I and III interferons have a demonstrated role in control of SARS-CoV-2 infection. The contribution of type II IFN, IFNγ, to protection or pathology during COVID-19 is less well understood. IFNγ and molecules induced by IFNγR signaling (e.g., CXCL10) have been associated with severe COVID-19 and the development of acute respiratory distress syndrome. Elevated levels of IFNγ also strongly correlate with the development of multi-system inflammatory syndrome in children after SARS-CoV-2 infection. In ACE2 transgenic mice, neutralizing IFNγ along with TNF reduced mortality of severe SARS-CoV-2 infection. However, IFNγ may also contribute to host-protection. IFNγ has been shown to inhibit SARS-CoV-2 replication in vitro. Administration of IFNγ to immunocompromised individuals with severe COVID-19 resulted in rapid declines in SARS-CoV-2 viral loads. In the mouse model, IFNγ is required for non-specific protection against SARS-CoV-2 observed after intravenous inoculation with the tuberculosis vaccine Bacillus Calmette–Guérin (BCG). Thus, IFNγ could contribute to protection or lung pathology during SARS-CoV-2 infection depending on the context.
Negative immune regulation also likely also has a key role in determining the outcome of coronavirus infection. In mice, the anti-inflammatory cytokine IL-10 has a protective role in coronavirus induced encephalitis. In humans with SARS-CoV-2 infection IL-10 has been associated with severe COVID-19 in multiple studies. IL-10 is upregulated early in disease progression, and along with IL-6, is a predictive biomarker for poor COVID-19 outcomes. However, a study in children reported that higher plasma IL-10 levels were correlated with decreased viral measurements in nasal aspirates. The mechanistic role of IL-10 and IFNγ in the rhesus macaque model of mild SARS-CoV-2 infection has yet to be determined.
In this rhesus macaque model of mild SARS-CoV-2 infection, we find that IL-10 and IFNγ have opposing effects on the development of lung lesions quantified with 18FDG-PET/CT imaging without an appreciable effect on SARS-CoV-2 replication. We identify a key role for IL-10 in negatively regulating the clonal expansion of virus-specific CD4 and CD8 T cells. Unexpectedly, we also find that IL-10 drives the differentiation of newly recruited airway effector CD4 and CD8 T cells into tissue resident memory T cells (Trm) after resolution of the infection and has a role in maintaining Trm in the nasal mucosa.
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