Influence of the Host and Parasite Strain on the Immune Response During Toxoplasma Infection

Abstract

Toxoplasma gondii is an exceptionally successful parasite that infects a very broad host range, including humans, across the globe. The outcome of infection differs remarkably between hosts, ranging from acute death to sterile infection. These differential disease patterns are strongly influenced by both host-and parasite-specific genetic factors. In this review, we discuss how the clinical outcome of toxoplasmosis varies between hosts and the role of different immune genes and parasite virulence factors, with a special emphasis on Toxoplasma-induced ileitis and encephalitis.

Targeted Transcriptomic Analysis of C57BL/6 and BALB/c Mice During Progressive Chronic Toxoplasma gondii Infection Reveals Changes in Host and Parasite Gene Expression Relating to Neuropathology and Resolution

“…Host genetics influence the outcome of Toxoplasma infection even if they do not prevent chronic infection. Thus, C57BL/6 mice are considered susceptible with high cyst burden that levels off around 30 days post infection ( Burke et al., 1994 ) while BALB/c mice, another commonly used mouse strain, are more resistant ( Supplementary Figure 1 ) ( Mukhopadhyay et al., 2020 ). While the increased resistance to infection in BALB/c mice has previously been linked to enhanced immune response specifically via MHC gene expression ( Brown et al., 1995 ), less is known regarding how neuropathology signatures differ between resistant BALB/c mice and the more susceptible C57BL/6 model over the course of chronic infection.…”

“…The establishment and maintenance of chronic infection involves complex changes as infection progresses from parasite entry and formation of cysts early during infection to long-term control of encysted parasites via immune cell recruitment and cytokine production leading to subtle worsening of neuropathology as infection progresses through the mid- and late chronic stages ( Liesenfeld et al., 1996 ; Denkers, 1999 ; Lee and Kasper, 2004 ; Lachenmaier et al., 2011 ; Feustel et al., 2012 ; Lilue et al., 2013 ; Hong et al., 2017 ; Radke et al., 2018 ; Graham et al., 2020 ; Mukhopadhyay et al., 2020 ). Our chosen timepoints represent each of these stages to capture as much directional change in gene expression as possible.…”

“…In addition, subtle neuropathology is commonly seen as noted by changes in morphology and function of both infected and non-infected neurons and changes in glia ( David et al., 2016 ; Graham et al., 2020 ). Control of infection is maintained for the lifetime of the host and pathology at this stage can vary depending on the genetics of the parasite as well as the background of the host ( Liesenfeld et al., 1996 ; Denkers, 1999 ; Lee and Kasper, 2004 ; Lilue et al., 2013 ; Mukhopadhyay et al., 2020 ). These changes in parasite phenotype, host immune response, and neuropathology have yet to be fully explored in the context of progressive chronic infection.…”

“…As with all infections, host genetic background plays an important role in disease and despite the ability of Toxoplasma to establish itself in almost all mammalian hosts, it has been known for some time that the development of disease is highly dependent on mouse strain, recently reviewed by Mukhopadhyay ( Blackwell et al., 1993 ; Johnson et al., 2002 ; Resende et al., 2008 ; Mukhopadhyay et al., 2020 ). Indeed, continuous culturing of Toxoplasma strains in vivo rely upon resistant and susceptible strains of mice to maintain virulence and cyst formation, something vitally important to maintain life cycle competency ( Goerner et al., 2020 ).…”

Seizing control: How dense granule effector proteins enable Toxoplasma to take charge

“…This acts as a way to rapidly alter host signal transduction mechanisms, such as preventing apoptosis and subverting innate immune responses, for example, through the action of a nuclear‐localized tyrosine kinase, ROP16 (Saeij et al., 2007; Yamamoto et al., 2009), which, depending on the allele present within a given strain, can phosphorylate host STAT3/6 in under a minute (Ong et al., 2010). The strain specificity of this effect is a common aspect of many of the most important effectors encoded within the Toxoplasma genome (Mukhopadhyay et al., 2020). Indeed, extreme variation in both sequence and copy number has been a characteristic that has led to the designation of many Toxoplasma proteins as candidate effectors.…”