Fig 1.
Ecological frameworks, and their translation toward within-host pathogen dynamics, including.
(A) Susceptible-Infected-Removed models, a class of consumer resource models where individuals (or target cells) are initially susceptible (blue box/line), then may become infected (red) on exposure to an infected individual (or virion) via transmission (arrow); they are then removed (green box, line), e.g., via mortality. Susceptible depletion (declining blue line) eventually means that the proportion infected ceases to grow (herd immunity threshold). Early events (e.g., earlier virus detection via TLR7 in females) will have disproportionate effects on the trajectory of viral growth by compounding impacts on exponential growth. (B) Predator-prey models also broadly reflect consumer resource models, here with parameters illustrating population cycling (rabbit populations collapse as wolf populations (and thus predation) increase; but once rabbit numbers are too low to sustain wolf populations, these in turn collapse, and so on). Within-host, such compensatory dependence could explain similar peak viral loads (prey) across hosts (males and females) with different immune system features (predators), although repeated cycling as depicted here is likely to be rare. (C) In collective action models, simple rules at the individual level result in population level information integration (e.g., fish schooling). This might shape immune cell population coordination (e.g., CD4 T-cell fate selection), and disruption of this signaling could contribute to immunopathology; and (D) Alternative Stable States emerge if gradual changes push the state of the community (or immune system) to contexts that complicate return to initial conditions. Here, pro-inflammatory cytokines show accelerating and then staturating growth beyond a threshold of viremia (purple line abruptly increases then flattens) while anti-inflammatory cytokines grow consistently (black line curves smoothly upwards). The growth and decline in the inflammation are equal at the 3 points where the lines intersect. At 2 of these (circles), inflammation grows if it falls, and shrinks if it increases, indicating stable equilibria that may be hard to escape; the square represents an unstable tipping point. Small differences in the timing and magnitude of viremia/the inflammatory response might push some individuals above this tipping point while others remain below, driving very divergent health outcomes in otherwise similar individuals.
Fig 2.
Dynamics of SARS-CoV-2 showing the hypothesized trajectory of viral load in the respiratory tract (bottom panel) for males (blue) and females (red). The top panel broadly maps a set of potential immune responses, roughly corresponding to recently described immunotypes [5]: Detecting and responding early (e.g., via early activation of type I Interferons) leading to early resolution, a delayed but ultimately successful response (e.g., via moderate Type 1 T cell activation), or an aberrant response resulting in hyperactivation (e.g., cytokine storms and exhaustion of lymphocytes) and the most severe forms of disease. Hosts of different sexes or ages might differ in propensity to follow the possible trajectories suggested in the top panel. For example, strong early detection and response in females or younger individuals (purple arrow labeled 1) could result in lower early viral loads. Despite delayed control, males or older individuals might still be able to regain the lost ground by successful development of cellular immunity (purple arrow labeled 2); if this response is greater for greater viral loads, this could ultimately result in similar scales of viral load in both slow and fast responding individuals around the peak of viral load. Finally, exhaustion/hyperactivation (of adaptive and innate arms of the immune system, respectively), potentially shaped by events early during infection (“path dependence,” such as failure of early interferon defenses or by comorbidities), could result in slower clearance in males or older individuals (purple arrow labeled 3 would correspond to females/younger individuals).