R01AI164727

Neisseria gonorrhoeae exploits host interferon epsilon to establish infection in the female urogenital tract - Project Abstract

Neisseria gonorrhoeae (NG) is a sexually-transmitted gram-negative bacterium that causes inflammation and pelvic inflammatory disease (PID). In the U.S., the incidence of NG is rising dramatically. Alarmingly, NG has become increasingly resistant to all approved antibiotics.

Interferon-epsilon (IFN-E) is a type I interferon that is highly expressed by epithelial cells of the female urogenital tract (both in mice and humans) but not in leukocytes. IFN-E, unlike the other type I interferons, is not induced by bacterial "pathogen-associated molecular patterns," such as lipopolysaccharides (LPS) or nucleic acids. Rather, IFN-E is regulated by sex hormones in the urogenital tract.

We discovered that estrogen contributes to NG infection by inducing the expression of IFN-E. Estrogen treatment dramatically prolongs NG infection of the female genital tract. Type I interferons, including IFN-E, share a common receptor, the IFN-alpha/beta receptor (IFNAR). Our data using IFNAR and IFN-E knockout (KO) animals, as well as blocking monoclonal antibodies to IFNAR, strongly support the hypothesis that estrogen-induced type I interferons contribute to NG immune evasion. In the absence of IFNAR signaling, NG is virtually incapable of maintaining colonization of the female urogenital tract. Furthermore, local administration of recombinant IFN-E (RIFN-E) protein completely reverted the phenotype to resemble the wild-type mice. Preliminary studies suggest that this may be related to regulation of cationic antimicrobial peptides (CAMP), such as CRAMP, as well as the sialylation of NG lipooligosaccharide (LOS).

We hypothesize that estrogen-induced IFN-E is required for productive NG infection because it regulates the availability of sialic acid precursors to NG sialyltransferase, thus allowing NG to evade AMP killing.

In Aim 1, we will assess the impact of estrogen and IFN-E on gene expression in epithelial cells in the female genital tract during infection using both mouse and human models of NG infection. We will use proteomics and gene expression approaches to determine if IFN-E regulates the expression of CAMPs and complement proteins in the genital tract.

In Aim 2, we will determine how IFNAR-expressing cell types promote NG survival. We will also assess the impact of type I interferon on the intrinsic bactericidal activity of phagocytes and their recruitment to the genital tract.

In Aim 3, we will assess the impact of IFN-E on NG genes, particularly genes that regulate CAMP evasion, and their impact on killing of NG in the absence of IFN-E. We will also determine if IFN-E reduces the sensitivity of NG to complement and/or CRAMP-mediated killing by regulating LOS sialylation.

The ability to modulate IFN responses during sexually-transmitted infections is a valid and potentially transformative strategy to ameliorate or prevent the damaging sequelae of NG infection and PID.

University Of Massachusetts Medical School

TO ASSIST PUBLIC AND PRIVATE NONPROFIT INSTITUTIONS AND INDIVIDUALS TO ESTABLISH, EXPAND AND IMPROVE BIOMEDICAL RESEARCH AND RESEARCH TRAINING IN INFECTIOUS DISEASES AND RELATED AREAS, TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS. TO ASSIST PUBLIC, PRIVATE AND COMMERCIAL INSTITUTIONS TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS, TO PROVIDE RESEARCH SERVICES AS REQUIRED BY THE AGENCY FOR PROGRAMS IN INFECTIOUS DISEASES, AND CONTROLLING DISEASE CAUSED BY INFECTIOUS OR PARASITIC AGENTS, ALLERGIC AND IMMUNOLOGIC DISEASES AND RELATED AREAS. PROJECTS RANGE FROM STUDIES OF MICROBIAL PHYSIOLOGY AND ANTIGENIC STRUCTURE TO COLLABORATIVE TRIALS OF EXPERIMENTAL DRUGS AND VACCINES, MECHANISMS OF RESISTANCE TO ANTIBIOTICS AS WELL AS RESEARCH DEALING WITH EPIDEMIOLOGICAL OBSERVATIONS IN HOSPITALIZED PATIENTS OR COMMUNITY POPULATIONS AND PROGRESS IN ALLERGIC AND IMMUNOLOGIC DISEASES. BECAUSE OF THIS DUAL FOCUS, THE PROGRAM ENCOMPASSES BOTH BASIC RESEARCH AND CLINICAL RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM EXPANDS AND IMPROVES PRIVATE SECTOR PARTICIPATION IN BIOMEDICAL RESEARCH. THE SBIR PROGRAM INTENDS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATES AND FOSTERS SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. RESEARCH CAREER DEVELOPMENT AWARDS SUPPORT THE DEVELOPMENT OF SCIENTISTS DURING THE FORMATIVE STAGES OF THEIR CAREERS. INDIVIDUAL NATIONAL RESEARCH SERVICE AWARDS (NRSAS) ARE MADE DIRECTLY TO APPROVE APPLICANTS FOR RESEARCH TRAINING IN SPECIFIED BIOMEDICAL SHORTAGE AREAS. IN ADDITION, INSTITUTIONAL NATIONAL RESEARCH SERVICE AWARDS ARE MADE TO ENABLE INSTITUTIONS TO SELECT AND MAKE AWARDS TO INDIVIDUALS TO RECEIVE TRAINING UNDER THE AEGIS OF THEIR INSTITUTIONAL PROGRAM.

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Worcester, Massachusetts 01655 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 388% from $813,011 to $3,970,913.