How does the nasal cavity's immune system combat SARS-CoV-2?

In a recent research paper uploaded to the bioRxiv preprint* server, researchers investigated the viral-clearing contributions of nasally-contained immune cells during severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) infection. Their study samples comprised C57BL/6 mice models infected with a wild COVID-19 sub-strain (B.1.351). Their findings highlight the crucial role of both CD4+ and CD8+ T cells in clearing viral infection via the secretion of Granzyme B, a cytotoxic molecule. Surprisingly, T cells are shown to play little role in defending the lungs against infection despite their remarkable ability to protect the nasal cavity. Finally, researchers used in-situ hybridization techniques to access the outcomes of CD-cell deprivation in immunocompromised mice.

Study: CD4+ and CD8+ T cells are required to prevent SARS-CoV-2 persistence in the nasal compartment. ​​​​​​​Image Credit: Chawalit Banpot / Shutterstock​​​​​​​Study: CD4+ and CD8+ T cells are required to prevent SARS-CoV-2 persistence in the nasal compartment. ​​​​​​​Image Credit: Chawalit Banpot / Shutterstock

*Important notice: bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Why do we need to research the intricacies of viral infections?

The global health and socioeconomic impacts of the ongoing coronavirus disease 2019 (COVID-19) pandemic are unprecedented, costing trillions in damages and claiming almost 7 million human lives. The outbreak is caused by SARS‑CoV‑2, a remarkably virulent distant cousin of the common flu and bird flu (H1N1). The virus is water-droplet-borne and infects the respiratory tract, where it displays a notable trait – the pathophysiology of the disease is determined by the site of prevalent infection. Infections restricted to the nasal passages typically present as milder infections, while those that infect the lungs can be life-threatening.

While studying the pathophysiology of interrelated organs (nasal cavity and lungs) in insolation has proven challenging in the past, the development of in vivo murine models and their capacity for gene-level tweaking to prevent external biases has enabled rigorous research into the transmission of immunity and pathology of many viruses.

Unfortunately, the ability of human ancestral SARS-CoV-2 to bind to murine spike protein has necessitated the development of COVID-19-specific transgenic mice strains like the human ACE2 (hACE2) transgenic mice. While this has allowed for evaluations of the mechanistic underpinnings of the worst disease outbreak of our time, the role of immune cells, especially those in the nasal cavity, in counteracting COVID-19 infection remains unknown.

About the study

In the present study, researchers investigated the functional role of CD4+ (helper) and CD8+ (cytotoxic) T cells against invading COVID-19 infection in both the upper- and lower respiratory tract. They used C57BL/6 transgenic mice for the experiments, which they infected with varying dosages (105 to 106 PFU) of the naturally occurring COVID-19 BA.1.351 subvarient. This intranasal inoculation allowed researchers to elucidate the immune response and infection kinetics triggered by COVID-19 infection.

To investigate the mechanistic, antigen-specific T-cell responses, evaluate their individual numbers, and measure their system-specific differences, isolated immune cells (nasal compartment, speel, and lung) were used in tandem with ex vivo peptide restimulation. Antibody-based depletion techniques were used to identify the outcomes of immune suppression on infection progress in the upper and lower respiratory systems. A TCID50 infectious virus assay was conducted to verify if any identified viral DNA in the nasal tract corresponded to the inoculated strain.

Genetic analyses were conducted to estimate the rate of viral genomic change over the few weeks of the study.

Study findings

Viral dose experiments reveal a reduction in murine weight corresponding to increased dosages. At 5 x 10PFU of viral load, the case-cohort was observed to lose 20% of its weight and 30% of its sample size. Viral kinetics experiments demonstrate that viral infectivity in the respiratory cavity starts rapidly, peaks between days two and four, and subsides to baseline by day 10. Antigenic response evaluations found evidence of viral infection in study subjects' upper and lower respiratory tracts.

Mirroring previous, non-COVID-related viral work, SARS-CoV-2 was shown to cause differing immune responses in each respiratory tract under study. Surprisingly, T cell activation in the lungs was minimal, as observed from ex vivo peptide restimulation results, suggesting a limited role for T cells in lung-associated infections. In contrast, T cell activities in the nasal cavity and respiratory network were profound and mainly involved the secretion of Granzyme B, a viral-suppressing metabolite.

CD4+ and CD8+ cells were observed to be crucial in the body's innate response against COVID-19 infection. However, redundancy between help and cytotoxic T cells was observed – COVID-19 infections remained mild if at least one of either CD4+ or CD8+ colonies survived the peak infection duration.

Experiments on immunocompromised mice reveal that COVID-19 infections require T helper and cytotoxic cells for viral clearing. In the absence of these cells, viral DNA in the nasal epithelium was found to persist for weeks or even months following initial inoculation. Crucially, viral persistence duration was directly proportional to increased viral diversity, suggesting that immunocompromised individuals might serve as a breeding ground for novel COVID-19 substrains. However, this trend is not without its limits – viral replication speed was found to reduce in tandem with increasing genetic diversity.

Conclusions

In the present study, researchers used genetically modified mice to investigate the impact of COVID-19 infections on both the upper and lower respiratory tracts and to elucidate the role of T cells in respiratory immune response. Their findings highlight that CD4+ and CD8+ T cells are crucial in combatting and withstanding the brunt of the COVID-19 infection, though this role is centered in the nasal cavity, with the lungs predominantly ignored.

The presence of either one of the CD4+ or CD8+ colonies was sufficient to prevent acute COVID-19 infection. If both cell populations were absent, viral persistence in the nasal passages was dramatically extended, which in turn resulted in increased viral differentiation, thereby compounding difficulties faced by researchers and pharmaceuticals in finding a cure that continues working.

*Important notice: bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
  • Preliminary scientific report. CD4+ and CD8+ T cells are required to prevent SARS-CoV-2 persistence in the nasal compartment. Meenakshi Kar, Katherine E.E. Johnson, Abigail Vanderheiden, Elizabeth J. Elrod, Katharine Floyd, Elizabeth Geerling, E. Taylor Stone, Eduardo Salinas, Stephanie Banakis, Wei Wang, Shruti Sathish, Swathi Shrihari, Meredith E. Davis-Gardner, Jacob Kohlmeier, Amelia Pinto, Robyn Klein, Arash Grakoui, Elodie Ghedin, Mehul S. Suthar. bioRxiv 2024.01.23.576505; DOI –  10.1101/2024.01.23.576505, https://www.biorxiv.org/content/10.1101/2024.01.23.576505v1
Hugo Francisco de Souza

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Hugo Francisco de Souza

Hugo Francisco de Souza is a scientific writer based in Bangalore, Karnataka, India. His academic passions lie in biogeography, evolutionary biology, and herpetology. He is currently pursuing his Ph.D. from the Centre for Ecological Sciences, Indian Institute of Science, where he studies the origins, dispersal, and speciation of wetland-associated snakes. Hugo has received, amongst others, the DST-INSPIRE fellowship for his doctoral research and the Gold Medal from Pondicherry University for academic excellence during his Masters. His research has been published in high-impact peer-reviewed journals, including PLOS Neglected Tropical Diseases and Systematic Biology. When not working or writing, Hugo can be found consuming copious amounts of anime and manga, composing and making music with his bass guitar, shredding trails on his MTB, playing video games (he prefers the term ‘gaming’), or tinkering with all things tech.

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