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Host-Pathogen Interactions Promoting Pathogen Survival and Potentiating Disease Severity & Morbidity in Invasive Group A Streptococcal Necrotizing Soft Tissue Infections

Chella Krishnan, Karthickeyan
http://orcid.org/0000-0002-4895-2495
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1446546952

Abstract Details

2015, PhD, University of Cincinnati, Medicine: Molecular Genetics, Biochemistry, and Microbiology.
Annually, 700 million non-severe cases of Group A Streptococcal (GAS) infections are reported worldwide and approximately 0.1% of these cases would emerge as severe infections. Despite the seriousness, and excessive morbidity and mortality associated with these infections, factors contributing to the emergence of hypervirulent GAS were not well understood. Inasmuch as GAS produce a wide variety of virulence factors, we focused on identifying host-pathogen interactions associated with the most severe and morbid manifestations of GAS infections. Specifically, we discovered that following localized GAS infections, the potent streptococcal cysteine protease (SpeB) is down regulated significantly, thereby preserving several GAS secreted virulence factors that are normally degraded by this protease. Consequently, this provides a favorable environment for the bacteria to persist and preserve its full battery of arsenal acquiring a hyper virulent phenotype. Efforts to dissect host-pathogen interactions involved in this transformation revealed that SpeB expression is modulated by human transferrin and/or lactoferrin-mediated iron chelation. Accordingly, we investigated the possible role of metals that are available at the host-pathogen interface in modulating SpeB expression and/or its proteolytic activity, and thereby potentiating GAS virulence. Indeed, we found that divalent metals, zinc and copper, inhibit the proteolytic activity of SpeB. Based on our findings, we propose that zinc and/or copper availability in the bacterial microenvironment can inhibit SpeB proteolytic activity, preserving the integrity of several GAS virulence factors essential for bacterial survival and dissemination within the host, and thereby exacerbating the severity of invasive GAS infections. Inasmuch as our research revealed that identical GAS bacteria can be isolated from patients presenting with starkly different severity, ranging from non-severe strep throat to severely morbid and life threatening necrotizing soft tissue infections (NSTIs), we undertook studies to determine if inter-individual genetic variations among infected subjects modulate the severity, manifestations and outcomes of GAS infections. To this end, we investigated the relative susceptibility of four conventional mice strains to GAS NSTIs, and found that among the strains tested, the DBA/2J mice were the most susceptible to severe NSTIs, associated with greater bacteremia, higher bacterial disseminations to spleen, and excessive production of inflammatory cytokines and chemokines, that lead to increased mortality. Additionally, we discovered that sex differences also contributed to variations in disease severity. Specifically, we found that female DBA/2J mice were relatively resistant to GAS infections compared to their male counterparts. To further dissect the host contributions to the NSTIs progression, we applied unbiased systems genetics approaches using a cohort of genetically diverse, advanced recombinant inbred (ARI) BXD strains. Using this approach, we were able to dissect the genetic architecture of NSTIs and identify four quantitative trait loci (QTL) on mouse chromosome (Chr) 2 (trait: survival), Chr 7 (trait: weight change), and Chr 6 and 18 (trait: lesion size). Additional differential expression analyses of genes within these four QTL revealed 211 differentially expressed genes in susceptible strains compared to 79 in resistant strains. Overall, the above findings enabled us to further appreciate the pivotal role of host genetic and sex differences in dictating outcomes of GAS infections.
Rhett Kovall, Ph.D. (Committee Chair)
George Deepe, M.D. (Committee Member)
Anil Jegga, D.V.M. M.Res. (Committee Member)
Malak Kotb, Ph.D. (Committee Member)
Yana Zavros, Ph.D. (Committee Member)
213 p.
Microbiology
Group A Streptococcus; Host-pathogen interactions; Host genetic context; Microbial pathogenesis; Pathogenesis and host response; Systems genetics

Recommended Citations

Citations

  • Chella Krishnan, K. (2015). Host-Pathogen Interactions Promoting Pathogen Survival and Potentiating Disease Severity & Morbidity in Invasive Group A Streptococcal Necrotizing Soft Tissue Infections [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1446546952

    APA Style (7th edition)

  • Chella Krishnan, Karthickeyan. Host-Pathogen Interactions Promoting Pathogen Survival and Potentiating Disease Severity & Morbidity in Invasive Group A Streptococcal Necrotizing Soft Tissue Infections. 2015. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1446546952.

    MLA Style (8th edition)

  • Chella Krishnan, Karthickeyan. "Host-Pathogen Interactions Promoting Pathogen Survival and Potentiating Disease Severity & Morbidity in Invasive Group A Streptococcal Necrotizing Soft Tissue Infections." Doctoral dissertation, University of Cincinnati, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1446546952

    Chicago Manual of Style (17th edition)

ucin1446546952
187
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This open access ETD is published by University of Cincinnati and OhioLINK.