Economic Game Theory to Model the Attenuation of Virulence of an Obligate Intracellular Bacterium

Abstract

Diseases induced by obligate intracellular pathogens have a large burden on global human and animal health. Understanding the factors involved in the virulence and fitness of these pathogens contributes to the development of control strategies against these diseases. Based on biological observations, a theoretical model using game theory is proposed to explain how obligate intracellular bacteria interact with their host. The equilibrium in such a game shows that the virulence and fitness of the bacterium is host-triggered and by changing the host's defense system to which the bacterium is confronted, an evolutionary process leads to an attenuated strain. Although, the attenuation procedure has already been conducted in practice in order to develop an attenuated vaccine (e.g., with Ehrlichia ruminantium), there was a lack of understanding of the theoretical basis behind this process. Our work provides a model to better comprehend the existence of different phenotypes and some underlying evolutionary mechanisms for the virulence of obligate intracellular bacteria.

Comparative Transcriptome Profiling of Virulent and Attenuated Ehrlichia ruminantium Strains Highlighted Strong Regulation of map1- and Metabolism Related Genes

“…This activation of ATP production needed for energy, but also for DNA synthesis, could have contributed to the shorter infectious cycle observed in vitro for the attenuated strains (4 days after infection), with intensive DNA replication beginning quickly after infection of new host cells (Marcelino et al, 2015 ; this study for the Senegal strain). This result is consistent with the economic game theory proposed by Tago and Meyer to explain the attenuation mechanism of obligate intracellular bacteria (Tago and Meyer, 2016 ). In fact, the authors explain that, in in vitro conditions, bacteria decrease the expression of genes related to virulence and, in parallel, increase the expression of genes related to metabolism, which results in a better fitness and a shorter development cycle.…”

Trends in mathematical modeling of host–pathogen interactions

“…Other asymmetric models focus on intracellular and persistent bacteria and gain insights into evolutionary advantages of attenuated virulence [124] or localization [36] as strategies of pathogenic bacteria. The opportunistic fungal pathogen C. albicans aroused attention due to its medical relevance and morphological switch from yeast-like to filamentous growth during infection.…”

Game Theory Applications in Host-Microbe Interactions:Mycobacterium tuberculosisinfection as an example

“…Bacteria and its host under stress may carry out the sophisticated principles of game theory, in order to decide whether to compromise or invade for elimination of the danger 4 . Rationality of game theory indicates that each player in a particular game is motivated by maximizing his own pay-off.…”

“…Rationality of game theory indicates that each player in a particular game is motivated by maximizing his own pay-off. Therefore, it is especially important for players to think about each other’s strategic choice and react accordingly 4 . Interactions between Mycobacterium tuberculosis ( Mtb) and human (players) are often included in the Mtb’s strategies to invade host responses, to replicate and persist within the host, and on the other hand, the host attempts to induce appropriate responses to eliminate the infection 5 .…”