Next-Generation Computational Genetic Analysis: Multiple Complement Alleles Control Survival after Candida albicans Infection

Abstract

Candida albicans is a fungal pathogen that causes severe disseminated infections that can be lethal in immunocompromised patients. Genetic factors are known to alter the initial susceptibility to and severity of C. albicans infection. We developed a next-generation computational genetic mapping program with advanced features to identify genetic factors affecting survival in a murine genetic model of hematogenous C. albicans infection. This computational tool was used to analyze the median survival data after inbred mouse strains were infected with C. albicans, which provides a useful experimental model for identification of host susceptibility factors. The computational analysis indicated that genetic variation within early classical complement pathway components (C1q, C1r, and C1s) could affect survival. Consistent with the computational results, serum C1 binding to this pathogen was strongly affected by C1rs alleles, as was survival of chromosome substitution strains. These results led to a combinatorial, conditional genetic model, involving an interaction between C5 and C1r/s alleles, which accurately predicted survival after infection. Beyond applicability to infectious disease, this information could increase our understanding of the genetic factors affecting susceptibility to autoimmune and neurodegenerative diseases.Genetic factors are known to alter susceptibility to and severity of Candida albicans infection in mice (1, 3, 22) and humans (42). Therefore, characterizing genetic factors affecting host susceptibility to C. albicans infection is of great importance. Since systemic candidiasis in mice closely resembles the human disease, inbred mouse strains provide a useful experimental model for identification of host susceptibility factors. Although virtually all organs are infected, the kidney is the major target, and the histopathology of infected lesions is similar in mice and humans. Mutations in several immune response genes have been associated with susceptibility to chronic mucocutaneous candidiasis in human families (14,17,36,48), and several have been verified in murine models. Differences in survival after hematogenous C. albicans infection among inbred mouse strains have been associated with complement factor 5 (Hc or C5) alleles (1, 2, 4, 34). A 2-bp deletion polymorphism at the 5Ј end of the C5 transcript shifts its reading frame and causes ϳ50% of inbred strains to be C5 protein deficient (54). Disseminated candidiasis is rapidly fatal in C5-deficient strains because of uncontrolled fungal proliferation in most organs (34). Although C5 alleles make an important contribution, several previous analyses indicated that there are other genetic factors that affect the severity of tissue damage or survival after C. albicans infection (2, 38). However, no one has yet been able to identify these other genetic factors.Since its inception in 2004, haplotype-based computational genetic mapping (HBCGM) (30) has been used to identify the genetic basis for many biomedical trait differences among inbred mou...

The Netrin-1 receptor DCC is a regulator of maladaptive responses to chronic morphine administration

“…Haplotype-based computational genetic mapping (HBCGM) was conducted as described previously [53], and used to identify those genomic regions whose genetic variation pattern was correlated with input phenotypic values for the 23 inbred strains utilized in these studies.…”

Candida Survival Strategies

“…Due to the relatively robust fungal cell wall it appears unlikely that the membrane attack complex affects Candida viability; however, complement-mediated opsonization enhances phagocytosis of fungal cells and killing by macrophages and neutrophils (reviewed in Rambach & Speth, 2009). The relevance of complement for the antiCandida response has been clearly demonstrated in mice, where strains with complement defects show a higher susceptibility to systemic candidiasis (Ashman et al, 2003;Mullick et al, 2004;Peltz et al, 2011;Tsoni et al, 2009). Like many bacterial pathogens, C. albicans has developed several mechanisms to interfere with complement activation (recently reviewed in Cheng, Joosten, Kullberg, & Netea, 2012;Luo, Skerka, Kurzai, & Zipfel, 2013).…”

Interplay between Candida albicans and the Mammalian Innate Host Defense

“…It was also demonstrated that C5-deficient mice are more susceptible to systemic C. albicans infection, resulting in a higher fungal burden in the organs (73). A recent study using computational analysis proposed that different combinations of C5 and C1r/s alleles can predict the survival of different mouse strains in the systemic Candida infection model (86). This implies that reduced C1 deposition in the susceptible mice resulted in reduced C5 binding and activation.…”