Distinct systemic and mucosal immune responses during acute SARS-CoV-2 infection

Abstract

Coordinated local mucosal and systemic immune responses following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection either protect against coronavirus disease 2019 (COVID-19) pathologies or fail, leading to severe clinical outcomes. To understand this process, we performed an integrated analysis of SARS-CoV-2 spike-specific antibodies, cytokines, viral load and bacterial communities in paired nasopharyngeal swabs and plasma samples from a cohort of clinically distinct patients with COVID-19 during acute infection. Plasma viral load was associated with systemic inflammatory cytokines that were elevated in severe COVID-19, and also with spike-specific neutralizing antibodies. By contrast, nasopharyngeal viral load correlated with SARS-CoV-2 humoral responses but inversely with interferon responses, the latter associating with protective microbial communities. Potential pathogenic microorganisms, often implicated in secondary respiratory infections, were associated with mucosal inflammation and elevated in severe COVID-19. Our results demonstrate distinct tissue compartmentalization of SARS-CoV-2 immune responses and highlight a role for the nasopharyngeal microbiome in regulating local and systemic immunity that determines COVID-19 clinical outcomes.

Microbiota and compartment matter in the COVID-19 response

“…Even though various viral proteins from SARS-CoV-2 can affect the expression of type I interferons in airway epithelial cells in vitro 4 , and interferons themselves might block viral replication, nasal interferon levels did not significantly correlate inversely with viral load. Nonetheless, this paper by Smith et al 1 , as well as another recent study that found increased expression of interferon-stimulated genes in the nasal epithelium of patients with mild or moderate COVID-19, but not in that of patients with severe COVID-19 5 , indicate the importance of local interferon responses in mucosa. Again, longitudinal analyses are needed to establish a critical role for these cytokines in reducing viral load and preventing severe disease progression.…”

“…Although SARS-CoV-2 infects predominantly the respiratory tract, the vast majority of studies thus far have investigated immune responses in blood. In the current issue of Nature Immunology, Smith et al use integrated analyses to characterize cytokines and antibodies in paired nasopharyngeal swab material and peripheral blood in a cross-sectional cohort of hospitalized patients at 8-12 days after symptom onset 1 . They associated these immunological parameters with disease severity, nasal and systemic SARS-CoV-2 viral load, and the nasal microbiome.…”

“…Investigating cytokine responses, Smith et al found several cytokines and immune system-relevant proteins that were increased in plasma of patients (VEGF, FGF, IL-1RA, IL-6, TNF, IL-10, CCL2, CXCL10, CCL3, CCL19, PD-L1, G-CSF and granzyme B), most of which showed an increasing concentration in plasma with increasing disease severity 1 . The antiviral cytokine IFN-α2 was present at lower levels in plasma of critically ill patients, as previously reported by this same group and others 3 .…”

SARS-CoV-2 hijacks neutralizing dimeric IgA for enhanced nasal infection and injury

“…However, it was noted that COVID-19 patients with acute respiratory distress syndrome (ARDS) had higher SIgA in the airway mucosa for unknown reasons 44 . Moreover, a recent study reported that SARS-CoV-2 viral loads were closely associated with spike-specific IgA responses in the nasal samples of acute COVID-19 patients 45 . Since dIgA were shown to be about 15 times more potent than mIgA in vitro against the same target, dIgA were suggested to be particularly valuable for therapeutic application against SARS-CoV-2 46 .…”

SARS-CoV-2 hijacks neutralizing dimeric IgA for enhanced nasal infection and injury

“…However, it was noted that COVID-19 patients with acute respiratory distress syndrome (ARDS) had higher SIgA in the airway mucosa for unknown reasons 44 . Moreover, a recent study reported that SARS-CoV-2 viral loads were closely associated with spike-speci c IgA responses in the nasal samples of acute COVID-19 patients 45 . Since dIgA were shown to be about 15 times more potent than mIgA in vitro against the same target, dIgA were suggested to be particularly valuable for therapeutic application against SARS-CoV-2 46 .…”