Host-pathogen Immune Feedbacks Can Explain Widely Divergent Outcomes from Similar Infections

Abstract

A longstanding question in infection biology is why two very similar individuals, with very similar pathogen exposures, may have very different outcomes. Recent experiments have found that even isogenic Drosophila melanogaster hosts, given identical inoculations of some bacterial pathogens at suitable doses, can experience very similar initial bacteria proliferation but then diverge to either a lethal infection or a sustained chronic infection with much lower pathogen load. We hypothesized that divergent infection outcomes are a natural result of mutual negative feedbacks between pathogens and the host immune response. Here we test this hypothesis in silico by constructing process-based dynamic models for bacterial population growth, host immune induction, and the feedbacks between them, based on common mechanisms of immune system response. Mathematical analysis of a minimal conceptual model confirms our qualitative hypothesis that mutual negative feedbacks can magnify small differences among hosts into life-or-death differences in outcome. However, explaining observed features of chronic infections requires an extension of the model to include induced pathogen modifications that shield themselves from host immune responses at the cost of reduced proliferation rate. Our analysis thus generates new, testable predictions about the mechanisms underlying bimodal infection outcomes.

Pathogen clonal expansion underlies multiorgan dissemination and organ-specific outcomes during murine systemic infection

“…In the latter, we observed an apparent inverse correlation with infectious dose, although more animals are required to reach statistical significance ( Figure 5A ). This trend suggests that more robust early immune induction (presumably elicited with a higher dose) disproportionately clears bacteria, a hypothesis that has also been generated by mathematical modeling ( Ellner et al, 2021 ; Duneau et al, 2017 ). Additionally, we observed apparent lobe (more frequent in the right lobe) and topological (all on the surface) biases in liver abscess formation, raising the possibility that anatomic differences between lobes and their relative locations contribute to apparently stochastic outcomes as some lobes may be more likely to be seeded (due to blood flow) and more permissive to bacterial replication.…”

Decomposing virulence to understand bacterial clearance in persistent infections

“…It is unclear how these bacteria are able to persist for so long inside the host, although there are a number of theoretical possibilities, for example, through surviving inside host tissue, forming biofilms or existing as persister or tolerant cells [75]. Salmonella typhimurium [76] and S. aureaus [77] can survive inside insect haemocytes.…”

The evolution of powerful yet perilous immune systems

“…For example, in fruit flies [ 71 ] and flour beetles [ 72 ], subtly divergent early dynamics ultimately determine whether the host will survive or die; in the fruit flies ( Drosophila melanogaster ) the relative rates of bacterial proliferation versus Imd -driven antimicrobial peptide production [ 73 ] immediately following Providencia rettgeri injection determined whether or not the fly would survive [ 71 ]. Mathematical modeling of mammalian immune dynamics suggests that such bifurcations also determine organism-scale Th cell phenotype [ 66 ], type I IFN responsiveness [ 74 ], and ultimately the chronicity of infection [ 75 , 76 ]. We eagerly look forward to experimental tests of these predictions in mammals.…”