SARS-CoV-2 Immunology and Therapeutics

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications, trials & patents

Abstract

We have completed the testing of SARS-CoV-2-infected rhesus macaques that were depleted of CD4+ or CD8+ T cells or dually depleted of both subsets and the results have been published (Hasenkrug et al. 2021). 6 macaques in each of 4 groups including a control non-depleted group have been analyzed. Nasal, throat and rectal swabs along with blood and bronchoalveolar fluids were collected in a kinetic manner over a period of 6 weeks and the animals were then re-infected to analyze anamnestic immune responses. The animals were then studied for an additional 2 weeks and were euthanized for harvesting of tissues for immunohistochemical study. Our study produced the rather surprising findings that neither CD4+ or CD8+ T cells were essential for the resistance of macaques to SARS-CoV-2 infection, nor were they required for strong anamnestic responses. In a collaboration with Dr. Mario Santiago, we investigated the best interferon subsets to control SARS-CoV-2 infections in vitro, and found IFN alpha 8 and 14 to be the most potent mediators of virus control. Furthermore, we found that variants of concern including alpha, beta, gamma and delta, had all developed significant resistance to interferon (Guo et al. 2021). This is important because the interferon response initiates many of the downstream immune responses critical to control SARS-CoV-2 in humans. Experiments are now in the works to test the resistance of the delta variant to interferon. Vaccine studies in aged mice are also underway in our laboratory with the goal of making elderly mice more reactive to vaccination and to develop stronger protective immunity. This is a collaboration with Dr. Irving Weissman at Stanford University who has developed a method to rejuvenate the immune systems of old mice, which, like humans, become less able to respond to new infections as they age, a phenomenon known as immune senescence. The rejuvenation experiments have been partially successful in that we have improved the vaccine-induced responses of aged mice significantly, but not to the extent of young mice. Finally, our project to develop aptamers that bind to SARS-CoV-2 spike protein receptor binding domain to block interactions with human ACE-2 has yielded more than a dozen aptamers with blocking activity. Unfortunately, Dr. Leonard Evans, who was leading this project, died during the experiments and we are currently re-evaluating how to proceed.