Can T Cells Abort SARS-CoV-2 and Other Viral Infections?

Abstract

Despite the highly infectious nature of the SARS-CoV-2 virus, it is clear that some individuals with potential exposure, or even experimental challenge with the virus, resist developing a detectable infection. While a proportion of seronegative individuals will have completely avoided exposure to the virus, a growing body of evidence suggests a subset of individuals are exposed, but mediate rapid viral clearance before the infection is detected by PCR or seroconversion. This type of "abortive" infection likely represents a dead-end in transmission and precludes the possibility for development of disease. It is, therefore, a desirable outcome on exposure and a setting in which highly effective immunity can be studied. Here, we describe how early sampling of a new pandemic virus using sensitive immunoassays and a novel transcriptomic signature can identify abortive infections. Despite the challenges in identifying abortive infections, we highlight diverse lines of evidence supporting their occurrence. In particular, expansion of virus-specific T cells in seronegative individuals suggests abortive infections occur not only after exposure to SARS-CoV-2, but for other coronaviridae, and diverse viral infections of global health importance (e.g., HIV, HCV, HBV). We discuss unanswered questions related to abortive infection, such as: 'Are we just missing antibodies? Are T cells an epiphenomenon? What is the influence of the dose of viral inoculum?' Finally, we argue for a refinement of the current paradigm that T cells are only involved in clearing established infection; instead, we emphasise the importance of considering their role in terminating early viral replication by studying abortive infections.

Keywords: SARS-CoV-2; T cell; abortive infection; adaptive immunity; seronegative.

Figure 1

Abortive infection in the spectrum of outcomes from first exposure to SARS-CoV-2. On exposure to SARS-CoV-2 there are a wide range of potential outcomes, such as: exposure without infection (due to sterilising immunity or a cellular genetic resistance); abortive infection, where a low level of infection provides sufficient antigen to expand pre-existing and de novo T cell responses. Abortive SARS-CoV-2 infection can also be identified by raised levels of the interferon stimulated gene, IFI27, in the blood [11]. Abortive infection occurs without induction of systemic antibodies to the virus or sufficient virus to be detectable by PCR. Alternative outcomes are: asymptomatic infection, where the virus and systemic antibodies are detectable in almost all individuals, but no symptoms are induced; symptomatic infection, as with asymptomatic infection, but with measurable symptoms ranging from mild, moderate to severe and fatal infection. Individuals who avoid exposure or have seen only non-infectious inocula, that could not lead to a replicative infection, are considered unexposed.

Figure 2

Schema of pre-existing memory T cells aborting infection without seroconversion. During classical acute-resolving virus infections there is a delay between infection and detection of both systemic virus-specific antibodies and T cells, as rare naïve precursors are recruited to the area of infection and draining lymph nodes where they go through several rounds of proliferation, which allows the virus time to exponentially replicate. Due to the association of abortive infection with the presence of pre-existing memory T cells targeting the replication-transcription complex of SARS-CoV-2, we hypothesis that these T cells could be rapidly recruited to, or be present at, the site of infection in the airways and can perform immediate effector functions blunting viral replication before infection is established. This could occur following a single exposure (¹) or due to low dose repetitive viral exposure (²), both of which would result in absence of detectable infection or seroconversion, but the expansion of SARS-CoV-2 specific T cells.