Orchestration Of Immune Response During COVID-19: Coordination of Local and Systemic Immunity Determines Clinical Outcomes

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly transmissible and pathogenic coronavirus known to infect humans. It is the causative agent of the ongoing  pandemic of acute respiratory disease, named “coronavirus disease 2019” (COVID-19) that was first detected in late 2019. Unfortunately, doctors and scientists do not know much regarding the exact mechanism and trajectory of infection of COVID-19 in patients. This is because the clinical manifestations of COVID-19 infection are highly variable and range from asymptomatic or mild symptoms to severe pneumonia that can result in death. It is unclear whether the disease progression is dependent on the viral pathogenicity, strength of the host immunity, to host co-morbidities, or if it is dependent on a combination of all these factors. Factors that influence and regulate both local and systemic immunity during early and late SARS-CoV-2 infection are also very poorly understood. However, what doctors and scientists have learnt is that early diagnosis of COVID-19 is the most critical step to treat infection. 

A study conducted by Smith et al. sought to explore why local mucosal and systemic immune responses following SARS-CoV-2 infection results in either protection or failure against COVID-19, thereby leading to a highly variable outcome in patients. To address this knowledge gap, they compared systemic and local immune responses during active SARS-CoV-2 infection in a well-characterized COVID-19 cohort that consisted of COVID-19 patients and healthy individuals as controls. Using an integrative approach, the authors characterized host antibody and cytokine responses, viral load and the nasopharyngeal, in other words of the area located behind the nose, microbiome profiles of the patients. The authors could demonstrate that distinct tissue compartmentalization of SARS-CoV-2 immune responses occur and that the nasopharyngeal microbiome plays a crucial role in regulating local and systemic immunity, and in determining COVID-19 clinical outcomes.

A robust systemic and mucosal antibody responses are generated in COVID-19 patients 

There is little information regarding how mucosal immunity is established and coordinated in patients with COVID-19. To answer this question, the authors compared immune responses in paired plasma (systemic) and nasopharyngeal (local) samples from patients with acute COVID-19. They observed a positive correlation between disease severity and plasma as well as nasopharyngeal neutralizing spike antibodies – such as IgA and IgG, found in mucous and all body fluids, respectively- in  patients with COVID-19. These results could corroborate previous knowledge that robust local and systemic humoral responses are generated against the SARS-CoV-2 spike protein in acute COVID-19 infection.

SARS-CoV-2 antibody responses are heterogenous in patients 

Since both plasma and nasopharyngeal mucosal spike-specific IgG and IgA antibody responses are generated in patients, the authors wanted to evaluate the relationship between both these responses in individuals with COVID-19. Interestingly, plasma and nasopharynx spike-specific antibody responses within the cohort were poorly correlated. Surprisingly, the spike-specific antibody profiles in the plasma and nasopharynx varied within the individual patients. Taken together, these observations suggest that mucosal or nasopharyngeal and systemic or plasma immune responses to COVID-19 infection are heterogeneous in nature and therefore are independently regulated.

Differential cytokine responses were compartmentalized during COVID-19

To explore the cellular mechanisms that influence mucosal and systemic spike-specific antibody responses to SARS-CoV-2, the authors measured concentrations of plasma and nasopharyngeal cytokines. As compared to the healthy controls, a significantly different cytokine profile was detected in patients. Interestingly, there was a distinct difference between the cytokine profile in the plasma and nasopharynx samples of patients. Of note, an enhanced inflammatory response and in contrast, a diminished interferon response was detected. These results suggest that nasopharyngeal cytokine responses are regulated in a distinct fashion. 

SARS-CoV-2 viral load may influence immune responses

To better understand the role of viral load in driving the immune responses, spike-specific antibody and cytokine responses were correlated with viral load. Analyses revealed that the plasma viral load had a strong association with systemic inflammatory cytokines that were elevated in severe COVID-19 in addition to the spike-specific neutralizing antibodies. In contrast, nasopharyngeal viral load was correlated with SARS-CoV-2 humoral responses, but inversely with interferon responses. These results indicate that the viral load may result in differential local and systemic immune responses. 

 COVID-19 infection may be associated with nasal microbiome perturbations

To evaluate the role of nasopharyngeal microbiomes during infection, nasopharyngeal bacterial profiles of the cohort were analyzed. Results indicated that bacterial load did not differ between patients and healthy controls. However, specific genera significant differences were detected and were drastically altered in a COVID-19 severity-dependent manner in patients. Furthermore, SARS-CoV-2 infection, either directly or indirectly, appeared to disrupt local microbial homeostasis, thereby  resulting in reduced levels of protective cytokines. In summary, a unique and an unexpected relationship between nasopharyngeal microbial communities and local as well as systemic, cytokine and antibody responses exists during SARS-CoV-2 infection.

Overall, this study demonstrates that a distinct tissue compartmentalization of SARS-CoV-2 immune responses exists in COVID-19 patients. It also highlights a unique role for the nasopharyngeal microbiome in regulating local and systemic immunity in determining COVID-19 clinical outcomes. The authors suggest that these findings would be helpful to doctors and scientists in developing new therapeutic strategies for the management of patients infected with SARS-CoV-2. 


This article summarizes work from Smith, N., Goncalves, P., Charbit, B. et al. Distinct systemic and mucosal immune responses during acute SARS-CoV-2 infection. Nat Immunol (2021). https://doi.org/10.1038/s41590-021-01028-7

Niyati Vachharajani is a research collaborator at University of North Carolina, Chapel Hill. Her twitter handle is @niyvac.

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