Well-balanced immune, inflammatory response hallmarks of asymptomatic COVID-19

Patients for whom the novel coronavirus disease (COVID-19) remains asymptomatic appear to mount a lower proinflammatory response to the virus, as well as a stronger systemic immune response, suggestive of better disease tolerance, according to a recent Singapore study.

“We comprehensively characterized the immune responses in asymptomatic SARS-CoV-2 infection and provided evidence that disease tolerance mechanisms are responsible for prevention/protection of immune-mediated pathologies,” the researchers said.

“While severe symptomatic infections resulted from various levels of immune dysregulation, the asymptomatic patients presented with more robust Th17 cell responses, a sustained neutralizing antibody response, and efficient tissue healing process during acute infection,” they added.

Thirty asymptomatic COVID-19 patients were enrolled and compared with 26 symptomatic patients (nine mild without pneumonia, 10 moderate without needing oxygen, and seven severe with oxygen requirement). All participants underwent transcriptomic, immune modulator, and cellular profiling.

During the acute phase of the infection, there were 215 under-expressed and 952 over-expressed genes in symptomatic patients. Gene Ontology suggested that asymptomatic patients had a weaker response to type-I interferon, innate, humoral, and classical complement immune responses, but had enriched activities as regards cellular killing, T-cell, and tumour necrosis factor (TNR) receptors, as well as the regulation of B cell proliferation during infection. [EMBO Mol Med 2021;13:e14045]

Plasma samples validated transcriptomic findings, showing higher levels of the brain-derived neurotrophic factor and vascular endothelial growth factor-D in asymptomatic patients. Levels of proinflammatory cytokines and markers of lung injury and regeneration were lower in asymptomatic patients.

“Together, these results suggest that the T-cell immunity and proinflammatory responses are differentially regulated in asymptomatic patients, suggesting reminiscence of disease tolerance,” the researchers said.

They then focused Th17, the subtype of helper T-cells for defence against microbes that the subsets Th1 and Th2 are not adapted to. Asymptomatic patients showed significantly more robust Th17 response than their symptomatic counterpart, further suggesting that this T-cell subtype plays an important role in COVID-19 disease progression.

Asymptomatic patients likewise had lower neutralizing antibody titres, though levels remained sufficient to neutralizing invading viruses.

“Although the manifestation of COVID-19 symptoms was limited in asymptomatic patients through well-balanced innate and adaptive immune responses, they were still infected with SARS-CoV-2 and could be a source of transmission. Forethought and caution should be exercised during mass immunization with novel vaccines, which are still not evaluated on their full efficacy on preventing virus transmission,” the researchers said.

“Nevertheless, our data highlight the importance of balance between antiviral inflammation, immune-modulation, and tissue repair responses at the early phase of infection, which may aid virus resolution, but yet limit development of symptoms in COVID-19,” they added.