GEM funding—Sept. 2016

GEM funded three pilot projects from the September 2016 round of applications. Find complete information on the GEM website.

GEM studies receiving seed funds

Determination of the global colonization prevalence of hypervirulent Klebsiella pneumoniae: An evolving "superbug" of increasing concern

  • Thomas Russo, MD
  • Peter Elkin, MD

A hypervirulent pathotype of Klebsiella pneumoniae (hvKP) is undergoing global dissemination from the Asian Pacific Rim (1, 2). In contrast to the usual healthcare-associated venue for “classical” K. pneumoniae (cKP) infections in the West, hvKP causes serious, life and organ threatening infections in younger, healthy individuals from the community and has the ability to metastatically spread from sites of infection (1, 3-5).

Further, hvKP are becoming increasingly antimicrobial resistant including acquisition of carbapenemases (6, 7). The prospect of a hypervirulent pathogen that is capable of causing severe infection in healthy, ambulatory individuals is alarming; the widespread evolutionary confluence of the hypervirulence of hvKP with the drug resistance of cKP is frightening. Colonization is the first step requisite for infection (8, 9), but a knowledge gap exists on the prevalence of this event.

Although all ethnic groups have suffered infection due to hvKP, individuals of Asian extraction appear to be disproportionately affected. Presently it is unknown whether this is due to more frequent geospecific exposure, an underlying genetic abnormality, the development of autoantibodies directed against an unknown host defense factor, high-density colonization, variable colonization resistance, or another factor. Establishing colonization prevalence and density at various geographic locales will assist in resolving these hypotheses and guide future direction.

We propose a novel approach to efficiently generate these critical data using a bioinformatics approach. These data will have inherent value by lending insights into the risk of hvKP infection, assisting in understanding its pathogenesis, identifying populations at risk, and generating insights on prevention. Further, these areas are fertile and critical topics for future study. Data generated from proposal will also serve as the foundation for successful external funding.

How pathogenic fungal microbes measure NAD+ levels to sense their nutrient environment and modulate genome architecture accordingly

  • Laura Rusch, PhD
  • John Panepinto, PhD
  • Tao Liu, PhD

Pathogenic fungi pose a serious danger to immunocompromised people. To establish an infection, these microbes interpret and respond to various nutrient environments in the host by establishing appropriate gene expression patterns.

One way of sensing nutrient availability is through the levels of common metabolites, which also serve as cofactors for enzymes that modulate genome architecture and gene expression. For example, the metabolite NAD+ is required by enzymes called sirtuins, which generate a compact chromatin state that represses gene expression. However, it remains poorly understood how metabolites such as NAD+ act as signaling molecules.

To elucidate this pathway, the goals of this project are to determine (i) which genes are regulated by sirtuins and hence are activated when intracellular NAD+ is low, and (ii) how nutrient availability in the environment influences intracellular NAD+ concentrations.

For these studies, we will focus on three pathogenic fungi that cause serious morbidity and mortality among immunocompromised people. These microbes must adapt to a variety of nutrient environments within a human host, and it is likely that sirtuins contribute to this process. These studies will advance our understanding of how NAD+ acts as an intracellular signaling molecule that is sensed and interpreted by sirtuins to enable cells to respond appropriately to their nutritional environment. In addition, this work will provide new insights into how pathogenic fungi colonize their human hosts. 

This collaborative project draws on our expertise in sirtuins (Rusche), fungal pathogenesis (Panepinto), and computational analysis of sequencing data (Liu).

Deciphering the evolutionary and biomedical relationships between human genetic variation, skin microbiome and autoimmune/inflammatory disorders

  • Omer Gokcumen, PhD 
  • Animesh Sinha, MD, PhD
  • Kristina Seiffert-Sinha, MD
  • Danel Gaile, PhD
  • David Tritchler, D.Sc 

Autoimmune and inflammatory disorders, including psoriasis and eczema, affect hundreds of millions of people. However, there are significant gaps in knowledge regarding the genetic and environmental causes underlying the susceptibility to these diseases. From an evolutionary perspective, skin harbors some of the most significant adaptations due to the wide range of environments that humans colonized.

Our preliminary data showed that genetic variants leading to these adaptations are associated both with autoimmune/inflammatory skin diseases and with microbial composition of the skin. Therefore, our central hypothesis is that adaptive human genetic variations involved in skin function are associated with susceptibility to autoimmune/inflammatory disorders through their influence on the skin microbiome by indirectly inducing specific immune responses.

To test this hypothesis, we will undertake a comprehensive strategy to analyze a) host genetic variation, b) transcriptomes, and c) microbiomes from non-affected and from affected skin samples from multiple psoriasis and eczema patients. Our proposal is innovative at three levels.

  • First, by combining evolutionary and biomedical perspectives, it will address why skin autoimmune/inflammatory disorders are common and not eliminated from the population by natural selection.
  • Second, it will incorporate underappreciated genomic structural variants, which are major contributors to disease susceptibility. Third, our sampling strategy and utilization of cutting edge -omics tools, will allow measuring the impact of host genetic variation to “healthy” and “affected” microbiomes in two common skin diseases. 

This innovative collaboration between two leading UB laboratories will lead to at least one major publication and preliminary data for an R01 grant.