Human influenza viruses replicate almost exclusively in the respiratory tract, yet infected individuals may also develop gastrointestinal symptoms, such as vomiting and diarrhea. However, the molecular mechanisms remain incompletely defined. Using an influenza mouse model, we found that influenza pulmonary infection can significantly alter the intestinal microbiota profile through a mechanism dependent on type I interferons (IFN-Is). Notably, influenza-induced IFN-Is produced in the lungs promote the depletion of obligate anaerobic bacteria and the enrichment of Proteobacteria in the gut, leading to a “dysbiotic” microenvironment. Additionally, we provide evidence that IFN-Is induced in the lungs during influenza pulmonary infection inhibit the antimicrobial and inflammatory responses in the gut during Salmonella-induced colitis, further enhancing Salmonella intestinal colonization and systemic dissemination. Thus, our studies demonstrate a systemic role for IFN-Is in regulating the host immune response in the gut during Salmonella-induced colitis and in altering the intestinal microbial balance after influenza infection.

Type I interferons (IFNs) are pleiotropic cytokines well recognized for their role in the induction of a potent anti-viral gene program essential for host defense against viruses. They also modulate innate and adaptive immune responses. However, the role of type I IFNs in host defense against bacterial infections is enigmatic. Depending on the bacterium, they exert seemingly opposite and capricious functions. In this review we summarize the effect of type I IFNs on specific bacterial infections and highlight the effector mechanisms regulated by type I IFNs in an attempt to elucidate new avenues to understanding their role.

Our ability to use ionizing radiation as an energy source, as a therapeutic agent, and, unfortunately, as a weapon, has evolved tremendously over the past 120 years, yet our tool box to handle the consequences of accidental and unwanted radiation exposure remains very limited. We have identified a novel group of small molecule compounds with a 4-nitrophenylsulfonamide (NPS) backbone in common that dramatically decrease mortality from the hematopoietic acute radiation syndrome (hARS). The group emerged from an in vitro high throughput screen (HTS) for inhibitors of radiation-induced apoptosis. The lead compound also mitigates against death after local abdominal irradiation and after local thoracic irradiation (LTI) in models of subacute radiation pneumonitis and late radiation fibrosis. Mitigation of hARS is through activation of radiation-induced CD11b+Ly6G+Ly6C+ immature myeloid cells. This is consistent with the notion that myeloerythroid-restricted progenitors protect against WBI-induced lethality and extends the possible involvement of the myeloid lineage in radiation effects. The lead compound was active if given to mice before or after WBI and had some anti-tumor action, suggesting that these compounds may find broader applications to cancer radiation therapy.

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 complement system has an important role in host resistance to systemic candidiasis but regulation of complement activation by C. albicans remains poorly defined. Previous studies have identified a requirement for naturally occurring antimannan IgG antibody in initiation of C3 opsonization of C. albicans through either the classical or alternative pathway. This study characterized antibodydependent initiation of the alternative pathway using the recombinant human monoclonal antimannan Fab fragment M1 and its full-length IgG1 antibody M1g1. Kinetic analysis of C3b deposition onto C. albicans with flow cytometry demonstrated the ability of M1g1 to restore the activity of either the classical or alternative pathway to the yeast-absorbed normal human serum, but the Fc-free M1 Fab restored only the activity of the alternative pathway. This Fc-independent, antimannan Fabmediated C3 deposition through the alternative pathway was also observed in a serum-free assay containing the six alternative pathway proteins and in C1q-or C2-depleted serum but not in factor B-depleted serum. M1-or M1g1-dependent alternative pathway initiation of C3b deposition occurred in an asynchronous manner at discrete sites that expanded to cover the entire cell surface over time as revealed with immunofluorescence microscopy, in contrast to a uniform appearance of initial C3 deposition through the classical pathway. Furthermore, antimannan Fab M1 promoted the assembly of the alternative pathway convertase on the cell surface seen as colocalization of C3 and factor B with immunofluorescence microscopy. Thus, human antimannan antibody has a distinct Fcindependent effector function in regulation of C3 deposition to C. albicans.