Mild SARS-CoV-2 infection in rhesus macaques is associated with viral control prior to antigen-specific T cell responses in tissues

Abstract

SARS-CoV-2 primarily replicates in mucosal sites, and more information is needed about immune responses in infected tissues. We used rhesus macaques to model protective primary immune responses in tissues during mild COVID-19. Viral RNA levels were highest on days 1-2 post-infection and fell precipitously thereafter. 18F-fluorodeoxyglucose (FDG)-avid lung abnormalities and interferon (IFN)-activated myeloid cells in the bronchoalveolar lavage (BAL) were found on days ~3-4. Virus-specific effector CD8 and CD4 T cells were detectable in the BAL and lung tissue on days ~7-10, after viral RNA, lung inflammation, and IFN-activated myeloid cells had declined. Notably, SARS-CoV-2-specific T cells were not detectable in the nasal turbinates, salivary glands, and tonsils on day 10 post-infection. Thus, SARS-CoV-2 replication wanes in the lungs prior to T cell responses, and in the nasal and oral mucosa despite the apparent lack of Ag-specific T cells, suggesting that innate immunity efficiently restricts viral replication during mild COVID-19.

mRNA-1273 vaccination protects against SARS-CoV-2–elicited lung inflammation in nonhuman primates

“…However, the kinetics of SARS-CoV-2 replication in rhesus macaques means that memory T cells are unlikely to have an opportunity to expand and traffic to the lung within the window of active viral replication. Even in naive animals, viral control is achieved prior to the development of tissue-specific SARS-CoV-2 T cell responses, and several studies have now shown that depletion of T cells in the macaque model only modestly affects viral control, especially in the setting of high levels of neutralizing antibodies (37,38).…”

Intranasal pediatric parainfluenza virus-vectored SARS-CoV-2 vaccine candidate is protective in macaques

“…Furthermore, S-specific (IFNγ + /TNFα + ) CD4 + and CD8 + T-cells from BAL could be separated into circulating CD69 - CD103 - and tissue-resident memory (Trm) CD69 + CD103 +/- subsets (Zheng and Wakim, 2021) (Figure 5, E and F for CD4 + T-cells and Figure 5, G and H for CD8 + T-cells, respectively). An additional subset of presumably tissue-resident S-specific CD4 + and CD8 + T-cells was identified as CD69 - CD103 + and has been previously detected in SARS-CoV-2-infected RMs (Nelson et al, 2022). Circulating CD69 - CD103 - S-specific CD4 + and CD8 + T-cells were detectable in BAL on day 9 pi and were prominent until day 14, representing about 60% of the S-specific T-cells on this day (Figure 5, F and H).…”

“…). An additional subset of presumably tissue-resident S-specific CD4 + and CD8 + T-cells was identified as CD69 -CD103 + and has been previously detected in SARS-CoV-2-infected RMs (Nelson et al, 2022). Circulating CD69 -CD103 -S-specific CD4 + and CD8 + Tcells were detectable in BAL on day 9 pi and were prominent until day 14, representing about 60% of the S-specific T-cells on this day (Figure 5, F and H).…”

Novel application of [18F]DPA714 for visualizing the pulmonary inflammation process of SARS-CoV-2-infection in rhesus monkeys (Macaca mulatta)

“…The relatively mild course of SARS-CoV-2 infection in macaques [26] might explain this different pattern of activation marker expression. The activation of these innate immune-cells could possibly contribute to the eradication of SARS-CoV-2 that was indeed shown to occur prior to onset of antigen specific T cell responses [27] . Interestingly, we observed that both increased TSPO activity as well as DC activation persisted for at least 30 days pi, despite clearance of the virus by day 10 pi.…”