Disentangling bacterial invasiveness from lethality in an experimental host‐pathogen system

Abstract

Quantifying virulence remains a central problem in human health, pest control, disease ecology, and evolutionary biology. Bacterial virulence is typically quantified by the LT 50 (i.e., the time taken to kill 50% of infected hosts); however, such an indicator cannot account for the full complexity of the infection process, such as distinguishing between the pathogen's ability to colonize versus kill the hosts. Indeed, the pathogen needs to breach the primary defenses in order to colonize, find a suitable environment to replicate, and finally express the virulence factors that cause disease. Here, we show that two virulence attributes, namely pathogen lethality and invasiveness, can be disentangled from the survival curves of a laboratory population of Caenorhabditis elegans nematodes exposed to three bacterial pathogens: Pseudomonas aeruginosa , Serratia marcescens, and Salmonella enterica . We first show that the host population eventually experiences a constant mortality rate, which quantifies the lethality of the pathogen. We then show that the time necessary to reach this constant mortality rate regime depends on the pathogen growth rate and colonization rate, and thus determines the pathogen invasiveness. Our framework reveals that Serratia marcescens is particularly good at the initial colonization of the host, whereas Salmonella enterica is a poor colonizer yet just as lethal once established. Pseudomonas aeruginosa , on the other hand, is both a good colonizer and highly lethal after becoming established. The ability to quantitatively characterize the ability of different pathogens to perform each of these steps has implications for treatment and prevention of disease and for the evolution and ecology of pathogens.

Heterogeneous shedding and susceptibility in aCaenorhabditis eleganstransmission model

“…S. enterica is a slow-killing intestinal pathogen of C. elegans (Aballay et al 2003; Aballay, Yorgey, and Ausubel 2000). There is a delay of several days post-infection before S. enterica -induced morbidity/mortality is observed (Biancalani and Gore 2019); on the time scale of our experiments, host death is essentially zero and can be neglected. Additionally, to demonstrate how shedding can differ across infectious agents, we measured shedding of the Gram-positive pathogen Staphylococcus aureus Newman (Begun et al 2005; Sifri et al 2003), and the native worm microbiome commensal Ochrobactrum MYb14 (Dirksen et al 2016; Zimmermann et al 2020).…”

Can the Cecal Ligation and Puncture Model Be Repurposed To Better Inform Therapy in Human Sepsis?

“…Perhaps it is time to consider that communities of pathogens that inhabit colonization surfaces of patients along the sepsis continuum have, over billions of years, evolved mechanisms to subvert and manipulate the host response even when selective host pathways are blocked (40). In an individual patient, the bacteria now present in the setting of critical illness have evolved multiple "work-arounds" to any immune/inflammatory blockade strategy informed by our current methods (41). It may be for this reason that anti-LPS, IL-RA, anti-TNF, and anti-TLR4, to name a few, have failed when applied to the most at-risk patients with sepsis and organ failure (42).…”