Pathogenesis of COVID-19 from the Perspective of the Damage-Response Framework

Abstract

The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents the medical community with a significant challenge. COVID-19 is an entirely new disease with disparate clinical manifestations that are difficult to reconcile with a single pathogenic principle. Here, we explain how the flexible paradigm of the "damage-response framework" (DRF) of microbial pathogenesis can organize the varied manifestations of COVID-19 into a synthesis that accounts for differences in susceptibility of vulnerable populations as well as for differing manifestations of COVID-19 disease. By focusing on mechanisms of host damage, particularly immune-mediated damage, the DRF provides a lens to understand COVID-19 pathogenesis and to consider how potential therapies could alter the outcome of this disease.

Keywords: COVID; viral pathogenesis; virus.

FIG 1

Pathogenesis of COVID-19 in the context of the DRF. The clinical manifestations of COVID-19 suggest there are three types of individual responses to SARS-CoV-2 infection (indicated as “I,” “II,” and “III” in the figure). Group I consists of individuals who mount an inadequate response to infection and cannot control the virus. For some such individuals, this leads to viral proliferation that triggers an exuberant inflammatory response (line leading from group I to group III). Group II consists of individuals who are asymptomatic or minimally symptomatic after infection with immune responses that effectively control the virus without mediating sufficient host damage to impair homeostasis. Group III consists of individuals that either mount an initial tissue-damaging response to SARS-CoV-2 infection or suffer progressive inflammatory damage as a result of unchecked viral replication in their lungs.

FIG 2

The states of COVID-19 infection. Considering damage as a function of time, the DRF posits that SARS-CoV-2-human host interaction results in the states of colonization or disease, which can lead to viral elimination and recovery or possibly to latency. A state of persistence or latency has not been associated with SARS-CoV-2 infection, although, theoretically, it could exist.

FIG 3

Effect of immune modulators on the position of an individual on the DRF parabola. For those with weak immune responses (left side of the x axis), treatment with an immune modulator that enhances immunity may move them to a position to the right representing reduced damage. Conversely, for those with disease resulting from immune-mediated host damage (right side of the x axis), treatment with an immune modulator that diminishes the intensity of the immune response may move them to a position to the left representing reduced damage.