Efficacy of low-dose oral use of type I interferon in cytomegalovirus infections in vivo

Oral administration of type I interferons (IFNs; murine IFN-α and IFN- β) reduces early replication of murine cytomegalovirus (MCMV) in both the spleen and liver of MCMV-infected BALB/c mice. Examination of a range of doses of IFN (1 to 1000 IU) showed that 10 IU administered daily for 1 week prior to virus infection was optimal for inhibition of MCMV replication. Furthermore, low-dose orally administered IFN (10 IU/day) was effective in mice challenged with lethal and sublethal virus inocula. The antiviral efficacy of low-dose orally administered IFN was not restricted by either the route of virus inoculation or the mouse genotype. Analysis by immunohistochemistry of IFN-α receptor-bearing cells of the gastrointestinal tract revealed predominant staining of perivascular smooth muscle and the lamina propria of the anterior tongue, small intestine and rectum. These tissues, dense in IFN-α receptor-bearing cells, are likely to be the sites of interaction of the orally administered IFNs with the mucosal immune system. In conclusion, we propose that low-dose oral use of type I IFN therapy may have broad applications in the treatment of CMV infections

Utility of mouse models in vaccine design and development

<p>The use of the mouse as the dominant animal model for immunologic studies was due in no small part to an inner ear defect in the Japanese waltzing mouse. The tendency of these mice to, when excited, scramble around the cage in a random fashion until exhausted is caused by a single recessive gene that causes an inner ear defect, leading to the curious behavior. In the process of maintaining this behavior through many generations of breeding, mouse fanciers unwittingly, but significantly, reduced the genetic heterogeneity of the species. This reduced heterogeneity made the growth of a tumor derived from a Japanese waltzing mouse far more reproducible. Utilizing this model and knowledge in the early 1900s, investigators began mating mice for many generations, creating inbred strains of mice with known susceptibility to various diseases. These studies led to the theory of the genetic control of tumor susceptibility, and, ultimately, to the use of mice to study what would eventually become the field of immunology.</p> <p>In this chapter, we discuss examples of clinically and/or experimentally relevant viral and bacterial infections that are used for the purposes of vaccine development and analysis.</p&gt

Supplementary Material for: Virulent <b><i>Francisella tularensis</i></b> Destabilize Host mRNA to Rapidly Suppress Inflammation

Highly virulent bacterial pathogens have evolved rapid means to suppress host inflammatory responses by unknown mechanisms. Here, we use virulent <i>Francisella tularensis</i>, the cause of lethal tularemia in humans, as a model to elucidate these mechanisms. We show that following infection of murine macrophages <i>F. tularensis</i> rapidly and selectively destabilizes mRNA containing adenylate-uridylate-rich elements that encode for cytokines and chemokines important in controlling bacterial infection. Degradation of host mRNA encoding interleukin (IL)-1β, IL-6 and CXCL1 did not require viable bacteria or de novo protein synthesis, but did require escape of intracellular organisms from endocytic vesicles into the host cytosol. The specific targeting of host mRNA encoding inflammatory cytokines and chemokines for decay by a bacterial pathogen has not been previously reported. Thus, our findings represent a novel strategy by which a highly virulent pathogen modulates host inflammatory responses critical to the evasion of innate immunity

GIMAP6 regulates autophagy, immune competence, and inflammation in mice and humans

Inborn errors of immunity (IEIs) unveil regulatory pathways of human immunity. We describe a new IEI caused by mutations in the GTPase of the immune-associated protein 6 (GIMAP6) gene in patients with infections, lymphoproliferation, autoimmunity, and multiorgan vasculitis. Patients and Gimap6(-/-) mice show defects in autophagy, redox regulation, and polyunsaturated fatty acid (PUFA)-containing lipids. We find that GIMAP6 complexes with GABARAPL2 and GIMAP7 to regulate GTPase activity. Also, GIMAP6 is induced by IFN-γ and plays a critical role in antibacterial immunity. Finally, we observed that Gimap6(-/-) mice died prematurely from microangiopathic glomerulosclerosis most likely due to GIMAP6 deficiency in kidney endothelial cells