The Zig-zag-model, a coevolutionary game of poker between host and pathogen–where survival is high stakes. The original plant focused concept described the relationship between adaptive traits for infection and defense. Here we fractionate the construct focusing solely on the evolutionary hallmarks of Yersinia spp. showing although challenged, this model remains widely useful.

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It is not unusual for plant-based research to lay foundations in host-pathogen understanding stimulating ideas such as the J. Jones and J. Dangl Zig-zag-model. The proposal describes an evolutionary response where bacteria and their hosts have acquired parallel methods to ensure fitness in each other’s presence. Bacterial flagellar adherence is one installation of this process. In response to the adaptation plants developed a receptor-based recognition system identifying similar structures as non-self, triggering protective action. To ensure survival within the host, bacteria then developed antigenic variation hiding from reactive elements perpetuating the infinite cyclic process. Although plant models display a larger variety of innate associated pathogen recognition tools, the process is fundamentally conserved enough in animal cells [1] to apply the model. Like plants animal cells utilize a variety of macro and micro immune functions from basal barriers to complex signaling. Although Yersinia spp. are not entirely adaptably unique, evolutionary analysis of the genus does create a clearer understanding.

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The majority of Yersinia spp. are environmentally sourced and non-pathogenic to humans. Thought to be the most important divergence factor into human pathogenicity, virulence plasmid pYV/CD1 encoding the type III secretion system (T3SS) twice independently evolved effectively splitting the pathogens into two distinct lineages, one encompassing both Yersinia pseudotuberculosis and Yersinia pestis, the other solely Yersinia enterocolitica [2]. Genetic divergence between Y. pseudotuberculosis and Y. pestis is marked by additionally acquired plasmids pFra/pMT1 and pPla/PCP1 as well as the promoter mutation inactivating pde3 in Y. pestis leading to unique virulence mechanisms such as flea infection [3]. The Y. pestis strains recovered from ancient teeth which date the most common ancestor of these two species back to the Bronze Age some 55,000 years ago, importantly note murine toxin gene Ymt is absent on the pFra/pMT1 plasmid [4]. The gene encodes phospholipase D which protects the bacterium while in the flea gut, allowing increased transmission rates at higher titers. It seems Ymt was acquired by horizontal gene transfer after human infection. This suggests Y. pestis was not only capable of infecting both humans and fleas earlier than previously thought but that the evolution thwarted hosts allowing a more suitable environment. It was also discovered the Pla outer membrane protease essential to deep tissue infection by both Y. pestis and Y. pseudotuberculosis has been lost more than once suggesting there is host-bacterium selective pressure causing variance [4].

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Applied selective pressures causing mutations in both host and pathogen is the foundation of the Zig-zag model and Yersinia spp. hold clues to its validity through the historic record. A consistent trait in pathogenic Yersinia spp. is the presence of flagella which is not present in host cells. Innate immune systems have devised toll like receptors (TLR) to identify pathogen presence from such pathogen-associated molecular patterns (PAMPs). Yet Y. pestis has matured to thwart this defense mechanism. The bacterium downregulates flagellar use at host core temperature to evade TLR identification. During the phagocytic process macrophage phagosomes acidify killing pathogens then localize TLR-3, TLR-7, TLR-9, and TLR-13 to the vacuolar membrane initiating inflammatory response through type 1 interferon and interferon- β. However, Y. pestis counters the acidification through unknown processes [5]. Innate immunity works in cohort and loss of any pathogen recognition receptor (PRR) results in the loss of type 1 interferon pathway but Y. pestis has devised a way to stimulate TLR-7 to its advantage without triggering the other PRRs [5]. Probably the most infamous virulence factor Y. pestis had devised is the T3SS delivery of outer membrane proteins (Yop) effectors. Yops play pleiotropic roles such as inhibiting essential Rho GTPases, disrupt actin cytoskeleton to prevent inconvenient phagocytosis, down regulate proinflammatory cytokines which attract immune cells and even induce cell death [3]. In extracellular conditions they up regulate lipopolysaccharide protein lipid A on a pseudocapsule to prevent phagocytic uptake [3]. Remarkably, with the incredibly complex processes of human innate immunity Y. pestis is able to either counter or avoid once establishing infection allowing it to be one of the deadliest pathogens known to man although it has not always been such. In this so-called Zig-zag-model Yersinia pestis is currently ahead but evolution history suggests this is merely the race it will once again need to fight if it wants to stay on top.