Immune lag is a major cost of prokaryotic adaptive immunity during viral outbreaks.

Jl Weissman,Jed A Fuhrman,Sean Meaden,Edze R Westra,Ellinor O Alseth

doi:10.1098/rspb.2021.1555

Abstract

Clustered regularly interspaced short palindromic repeat (CRISPR)-Cas adaptive immune systems enable bacteria and archaea to efficiently respond to viral pathogens by creating a genomic record of previous encounters. These systems are broadly distributed across prokaryotic taxa, yet are surprisingly absent in a majority of organisms, suggesting that the benefits of adaptive immunity frequently do not outweigh the costs. Here, combining experiments and models, we show that a delayed immune response which allows viruses to transiently redirect cellular resources to reproduction, which we call ‘immune lag’, is extremely costly during viral outbreaks, even to completely immune hosts. Critically, the costs of lag are only revealed by examining the early, transient dynamics of a host–virus system occurring immediately after viral challenge. Lag is a basic parameter of microbial defence, relevant to all intracellular, post-infection antiviral defence systems, that has to-date been largely ignored by theoretical and experimental treatments of host-phage systems.

Highlights

Clustered regularly interspaced short palindromic repeat (CRISPR)-Cas immune systems are the only known form of adaptive immunity found in prokaryotic organisms [1,2]
We found that during outbreaks of novel viruses immune lag can be extremely costly, leading to selection for an surface mutant (SM) defence strategy over a CRISPR strategy, even when the SM strategy comes with a growth cost
We found that if strong upregulation occurs after infection, so that the resulting ‘fast immune’ cells with an upregulated CRISPR locus do not experience lag, the overall effects of immune lag can largely be mitigated during an outbreak

Summary

Introduction

Clustered regularly interspaced short palindromic repeat (CRISPR)-Cas immune systems are the only known form of adaptive immunity found in prokaryotic organisms [1,2]. We combined experiments and mathematical models to investigate how lag transiently alters the costs of CRISPR-Cas during a viral outbreak, and found that when viruses invade a primarily susceptible host population with a small sub-population of CRISPR-immune host even the CRISPR-immune cells face a large virus-induced reduction in fitness. We consider the case where this overproduction of CRISPR-Cas defence complexes allows the host to degrade viral genetic material before it can be expressed, avoiding any immune lag We implemented this scenario (electronic supplementary material, figure S6) by letting recently immunized and lagged cells pass into a ‘fast’ immunity (CF) state where the CRISPR-Cas system does not experience immune lag because the cas targeting genes are upregulated: C_ F 1⁄4 BBB@zzgfflrvþ}oRw|fflRt{h À zf}lwo|w{CCCACF immzffluffl}n|izfflffla{tion clzea}r|an{ce downzr}eg|u{lation þ mdVS þ fL À zCF , ð2:5Þ and modified the equation for immune host :. Here we assume that cells return from the transcriptionally upregulated state (CF) to the baseline state (C) at a constant rate (ζ), though relaxing this assumption has little effect on the qualitative results of the model (electronic supplementary material, Text S5 and figure S7)

Results

Discussion

Findings

42. Brum JR et al 2015 Patterns and ecological drivers