Genetic Dissection of the Host Tropism of Human-Tropic Pathogens

Abstract

Infectious diseases are the second leading cause of death worldwide. Although the host multitropism of some pathogens has rendered their manipulation possible in animal models, the human-restricted tropism of numerous viruses, bacteria, fungi, and parasites has seriously hampered our understanding of these pathogens. Hence, uncovering the genetic basis underlying the narrow tropism of such pathogens is critical for understanding their mechanisms of infection and pathogenesis. Moreover, such genetic dissection is essential for the generation of permissive animal models that can serve as critical tools for the development of therapeutics or vaccines against challenging human pathogens. In this review, we describe different experimental approaches utilized to uncover the genetic foundation regulating pathogen host tropism as well as their relevance for studying the tropism of several important human pathogens. Finally, we discuss the current and future uses of this knowledge for generating genetically modified animal models permissive for these pathogens.

Keywords: animal models; bacteria; genetic engineering; humanized mice; pathogen host tropism; virus.

Figure 1

Diversity of pathogen host tropism. Viruses, bacteria, and parasites vary in their respective host ranges, with some only able to infect humans (red) while others can infect a wide range of vertebrates and invertebrates (purple). Each color, from red to purple, represents a particular level of host range diversity. Text included in colored rectangles indicates the animal groups included in each host range level. Only a few examples of pathogens are indicated for each level. The level of human-restricted pathogens (red) is enlarged as a red circle. Abbreviations: CCHFV, Crimean-Congo hemorrhagic fever virus; CMV, cytomegalovirus; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV-1, human immunodeficiency virus 1; HHVs, human herpes viruses; HEV, hepatitis E virus; TBEV, tick-borne encephalitis virus; VEEV, Venezuelan equine encephalitis virus.

Figure 2

Identification and applications of regulators of human-tropic pathogens. A graphic summary of the different methods used to discover host (orange) and viral (blue) determinants that regulate pathogen host tropism is shown. In some cases, the search for host factors can be guided by preliminary experiments, such as those using interspecies heterokaryons. In the absence of initial guiding experiments, whole-genome screening methods can be applied. The identification of pathogen factors can be determined via the screening of pathogen determinants (e.g., viral proteins, amino acids) by genome engineering (pathogen engineering), or pathogens can be serially passaged in a nonpermissive host to detect mutations that increase pathogen fitness (pathogen adaptation). The uncovering of host factors may also allow the generation of genetically modified pathogens able to overcome potential host restriction factors (dotted line). Collectively, the identification of host factors regulating the tropism of human pathogens, combined with the development of several genetic tools, can allow the generation of genetically humanized mice (or other suitable animal models) permissive for human-tropic pathogens. Such animal models represent a promising platform for the study of human-tropic pathogens in vivo, as well as for the development of vaccines or therapeutic strategies against challenging pathogens. Abbreviations: HBV, hepatitis B virus; HCV, hepatitis C virus.