Disease severity in coinfected hosts: the importance of infection order

When hosts are simultaneously infected by different pathogens, the
severity of the disease might be exacerbated compared to hosts harboring
single infections. The reasons underlying these changes in parasite
virulence are manifold. Here, we investigated the importance for the
infection outcome of order and timing of infection. We used a model of
rodent coinfection between two parasites that do not compete for common
resources, an intestinal nematode (Heligmosomoides polygyrus) and an
apicomplexan protozoan (Plasmodium yoelii). During single infections, H.
polygyrus induced only mild disease symptoms. Plasmodium produced a
substantial reduction in the number of red blood cells, but all mice
recovered from the infection. A different picture emerged in coinfected
hosts. Heligmosomoides maintained a profile of mostly asymptomatic
infection whatever the order of the infection (first or second). On the
contrary, P. yoelii incurred substantially higher costs in hosts that had
been previously infected with H. polygyrus (independently of the timing of
infection). We then investigated the possible reasons underlying the
increase of Plasmodium virulence in coinfected hosts. We found that
coinfected hosts were less able to control Plasmodium multiplication and
to recover from infection-induced anemia. Coinfected hosts had similar
levels of erythropoietin and similar renewal of lost red blood cells,
resulting in decreased tolerance to Plasmodium infection. Experimental
administration of erythropoietin in coinfected hosts, partially decreased
the severity of disease symptoms and improved tolerance. The
detoxification of free heme released during the lysis of red blood cells,
and the expression of Th1 and anti-inflammatory cytokine genes were also
similar between coinfected and single infected hosts. However, coinfected
mice had higher proportions of regulatory T cells expressing the CTLA-4
immune checkpoint, suggesting an enhanced immunosuppressive activity of T
regs. Plasmodium infection also induced the exhaustion of CD8+T cells, as
coinfected mice had higher proportions of both PD-1+and LAG-3+CD8+T cells,
and an increase in the CD4+/CD8+ratio. Overall, these results stress the
importance of the order of infection as a major determinant of disease
severity in coinfected hosts. We discuss the possible epidemiological and
evolutionary consequences of these results.