The Effect of Immunodeficiency on the Evolution of Virulence: An Experimental Test with the Rodent MalariaPlasmodium chabaudi

Abstract

Host immunity plays an important role in the evolution of pathogen virulence and disease emergence. There is increasing theoretical and empirical evidence that enhanced immunity through vaccination may have the unfortunate side effect of selecting for more virulent parasites, but the effect of host immune suppression on pathogen evolution is less clear. Here, we use serial passage experiments in mice to test how immune-suppressed hosts may alter pathogen virulence evolution. We passaged Plasmodium chabaudi through CD4(+) T cell-depleted or control mice every 7 days for 20 weeks and then measured virulence differences during infection of immunologically normal mice. We found that those parasites that had been selected through CD4(+) T cell-depleted mice were more virulent than parasites selected through control mice. Virulence increases during serial passage are believed to be caused by pathogen adaptation to the passage host. These data suggest that immune-suppressed hosts could provide a within-host environment that lowers the barrier to parasite adaptation and promotes the evolution of virulence.

Eimeria falciformisBayerHaberkorn1970 and novel wild derived isolates from house mice: differences in parasite lifecycle, pathogenicity and host immune reactions

“…This phenomenon has been demonstrated in systems including the apicomplexan parasites Plasmodium spp. in rodents Read, 1999, 2004;Barclay et al, 2014).…”

Generalized selection to overcome innate immunity selects for host breadth in an RNA virus

“…This phenomenon has been observed in populations of Plasmodium malarial parasites, when passaged in immuno‐compromised mice (Barclay et al. ). The relaxed selection against the parasite population in the immune‐deficient host environment allowed for a correlated vaccine‐resistant pathogen genotype to emerge.…”

“…Recent theoretical evidence demonstrates that immuno-compromised hosts may allow for enhanced within-host pathogen diversity, thereby increasing the likelihood that such hosts could transmit a spontaneous hyper-virulent influenza variant (Reperant et al 2014). This phenomenon has been observed in populations of Plasmodium malarial parasites, when passaged in immuno-compromised mice (Barclay et al 2014). The relaxed selection against the parasite population in the immunedeficient host environment allowed for a correlated vaccineresistant pathogen genotype to emerge.…”

Competitive exclusion strengthens selection for transmissibility and increases the benefit of recombination for within-host adaptation

“…Relaxing selection for transmission, however, selects for within-host fitness without consideration for transmissibility. Serial passage experiments in mice, for example, have resulted in the inactivation of genes that promote transmission at the expense of within-host fitness, such as dltB in S. pneumoniae [30], or selected for accelerated growth in Plasmodium chabaudi [31, 32]. Analogous dlt inactivation and evolution of more virulent Plasmodium knowlesi parasites have also been observed during human infections, suggesting that within-host adaptation has important consequences for disease severity and warranting further study of how transmission affects the rate of such adaptation [11, 33].…”