CD4(+) T-cells are important in regulating macrophage polarization in C57BL/6 wild-type mice.

During activation, macrophages undergo physiological changes affecting their surface protein expression and cytokine production and have been subsequently categorized into M1 (classically-activated) and M2 (alternatively-activated) macrophages. It remains unclear which lymphocyte population provides the immune microenvironment to regulate macrophage polarization. In this study, we establish a functional and phenotypic profile of peritoneal macrophages from C57BL/6 wild-type mice. We also showed that Rag1(-/-) and Rag2(-/-)γc(-/-) mice have similar, exaggerated M1 characteristics in comparison to control mice, suggesting that NK and/or NK-T cells may not be essential in this process. By controlling for environmental factors, we determine that lymphocyte-derived cytokines, rather than inherent properties of macrophages themselves, are crucial for their regulation. Lastly, we report that macrophages from CD4(-/-) mice display an M1 profile, suggesting that CD4(+) T-cells play a dominant role over other lymphocyte populations in providing the cytokine environment for regulating macrophages towards an M2 profile under normal wild-type conditions.

Humanized mice are susceptible to Salmonella typhi infection.

Salmonella enterica serovar Typhi is a pathogen that only infects humans. Currently, there is no animal model for studying this pathogen. Recently, alymphoid RAG-2(-/-)/γ(c)(-/-) mice engrafted with human leukocytes, known as humanized mice, have been successfully utilized to develop experimental models for several human-specific viral infections, including HIV, human-like dengue fever and hepatitis C virus. Little is known about the usefulness and feasibility of the humanized mouse model for the study of human-specific bacterial pathogens, such as S. typhi. The aim of this study was to determine if Salmonella enterica serovar Typhi could establish productive infection in humanized mice. Here we report that intravenous inoculation of S. typhi into humanized mice, but not controls, established S. typhi infections. High bacterial loads were found in the liver, spleen, blood and bone marrow of mice reconstituted with human leukocytes, but not in the unreconstituted control mice. Importantly, S. typhi-infected humanized mice lost significant body weight, and some of the infected mice displayed neurological symptoms. Our data suggest, for the first time, that humanized mice are susceptible to S. typhi challenge and that this model can be utilized to study the pathogenesis of S. typhi to develop novel therapeutic strategies.

Characterization and IL-15 dependence of NK cells in humanized mice.

Natural Killer cells can distinguish between healthy and malignant cells and have the unique ability to lyse tumour cells without prior sensitization. Differences between murine and human NK cells complicate the translation of this knowledge into useful therapeutics. Humanized mouse models that support the development of human leukocytes are a promising avenue of research that aims to address this problem. Here we provide an in-depth phenotypic analysis of human NK cells in Balb/c Rag2(-/-)γ(c)(-/-) mice reconstituted with human hematopoietic stem cells. We have examined the development of NK cells in bone marrow, thymous, spleen, lymph node (LN) and liver. Interestingly, in naive reconstituted mice, NK cells were found in thymus and LN, but not in bone marrow. These NK cells expressed several inhibitory and activating receptors needed for malignant cell detection. Furthermore, we confirm that administration of recombinant human interleukin-15 (rhIL-15) or Ad-vector expressing hIL-15 is able to significantly enhance NK cell development and maturation, particularly in bone marrow and liver, in this model. Our results suggest that human NK cells developed in mice may have phenotypes and tissue distributions similar to those seen in human.

Humanized mice for Salmonella typhi infection: new tools for an old problem.

Salmonella enterica serovar Typhi (S. typhi), is a human restricted pathogen and the causal agent of typhoid fever. Although the use of antimicrobial drugs or vaccines has served as an effective therapeutics strategy against typhoid fever, the recent surge in multidrug resistant strains of S. typhi presents a major health concern worldwide. Progress on typhoid research has been limited in the past due to the lack of a suitable animal model that recapitulates the hallmark immunological features of human typhoid fever. We have recently developed a humanized immune system (HIS) mouse model that after intravenous challenge with S. typhi displayed classical manifestations of human typhoid fever including meningitis, liver pathology and mortality. Concurrent to our studies, two other groups also have developed humanized mouse models of S. typhi infections employing different protocols. All these recently adopted animal models of S. typhi infections provide promise for a new era of S. typhi research that may expedite detailed understanding of the cellular and molecular mechanisms of this bacterial infection and investigations of new antimicrobials and vaccines for effective control.