Host circadian rhythms are disrupted during malaria infection in parasite genotype-specific manners

Kimberley F Prior,Aidan J O’Donnell,Daan R Van Der Veen,Nicholas J Savill,Sarah E Reece,Samuel S C Rund

doi:10.1038/s41598-019-47191-8

Abstract

Infection can dramatically alter behavioural and physiological traits as hosts become sick and subsequently return to health. Such “sickness behaviours” include disrupted circadian rhythms in both locomotor activity and body temperature. Host sickness behaviours vary in pathogen species-specific manners but the influence of pathogen intraspecific variation is rarely studied. We examine how infection with the murine malaria parasite, Plasmodium chabaudi, shapes sickness in terms of parasite genotype-specific effects on host circadian rhythms. We reveal that circadian rhythms in host locomotor activity patterns and body temperature become differentially disrupted and in parasite genotype-specific manners. Locomotor activity and body temperature in combination provide more sensitive measures of health than commonly used virulence metrics for malaria (e.g. anaemia). Moreover, patterns of host disruption cannot be explained simply by variation in replication rate across parasite genotypes or the severity of anaemia each parasite genotype causes. It is well known that disruption to circadian rhythms is associated with non-infectious diseases, including cancer, type 2 diabetes, and obesity. Our results reveal that disruption of host circadian rhythms is a genetically variable virulence trait of pathogens with implications for host health and disease tolerance.

Highlights

Circadian rhythms include endogenous and entrainable oscillations in physiology and behaviour with a duration of about 24 hours[1]
Are our measured host circadian rhythms altered in a parasite-genotype dependent manner throughout the entire infection – from the asymptomatic phase, through increasing severity of sickness symptoms, and the return to health? Second, is parasite-genotype dependent disruption to host rhythms associated with their varying levels of virulence and replication rates? We find that: (i) disruption to locomotor activity and body temperature rhythms occurs during infection in a parasite-genotype dependent manner; (ii) virulent genotypes are associated with more severe effects on host rhythms; (iii) locomotor activity and body temperature rhythms can change independently; and (iv) rhythm disruption is only explained in part by variation in the severity of anaemia or parasite density induced by each genotype
Zeitgeber Time (ZT) which is the number of hours since lights on (ZT0) and ZT12 is the start of lights off. (b) Mean ± SEM levels of locomotor activity or body temperature during night time or daytime for the infection segments (N ≤ 5 per genotype: green = AJ, orange = AS, blue = DK)

Summary

Introduction

Circadian rhythms include endogenous and entrainable oscillations in physiology and behaviour with a duration of about 24 hours[1]. Environmental time-of-day information is received by the suprachiasmatic nuclei (SCN) of the hypothalamus, known as the central clock, via the retinohypothalamic tract. This is transmitted to peripheral clocks in the rest of the body, likely via outputs such as body temperature rhythms and hormone levels. We follow infections with three genetically distinct genotypes of the murine malaria parasite, Plasmodium chabaudi, and quantify rhythms in a host behavioural trait (locomotor activity) and a physiological trait (body temperature) (see Fig. 1 for experimental design). We couple the relative ease of tracking parasite dynamics and host rhythms during malaria infection with a new technology to non-invasively monitor locomotor activity and body temperature rhythms throughout complete infection cycles at high temporal resolutions. Note in B the line break on day 9–10 PI for the AJ genotype which represents missing data

Methods

Results

Conclusion