The pathogenesis of experimental cerebral malaria (ECM) is an immunologic process, mediated in part by Th1 CD4+ T cells. However, the role of the Th1 CD4+ T cell differentiation program on the ability to control parasitemia and susceptibility to ECM disease during blood stage malaria has never been assessed directly. Using the Plasmodium berghei ANKA murine model of ECM and mice deficient for the transcription factor T-bet (the master regulator of Th1 cells) on the susceptible C57BL/6 background, we demonstrate that although T-bet plays a role in the regulation of parasite burden, it also promotes the pathogenesis of ECM. T-bet−deficient (Tbx21−/−) mice had higher parasitemia than wild type controls did during the ECM phase of disease (17.7 ± 3.1% versus 10.9 ± 1.5%). In addition, although 100% (10/10) of wild type mice developed ECM by day 9 after infection, only 30% (3/10) of Tbx21−/− mice succumbed to disease during the cerebral phase of infection. Resistance to ECM in Tbx21−/− mice was associated with diminished numbers of IFN-γ–producing CD4+ T cells in the spleen and a lower accumulation of CD4+ and CD8+ T cells in the brain. An augmented Th2 immune response characterized by enhanced production of activated GATA-3+ CD4+ T cells and elevated levels of the eotaxin, MCP-1, and G-CSF cytokines was observed in the absence of T-bet. Our results suggest that in virulent malarias, immune modulation or therapy resulting in an early shift toward a Th2 response may help to ameliorate the most severe consequences of malaria immunopathogenesis and the prospect of host survival.

Tularemia is a zoonotic disease caused by the Category A bioterrorism agent Francisella tularensis. In Scandinavia, tularemia transmission by mosquitoes has been widely cited in the literature. We tested >2,500 mosquitoes captured in Alaska and found Francisella DNA in 30% of pooled samples. To examine the potential for transmission of Francisella by mosquitoes, we developed a mosquito model of Francisella infection. Larvae of Anopheles gambiae Giles and Aedes aegypti (L.) readily ingest F. tularensis but do not efficiently transfer infective doses of the bacterium to the pupal or adult stage. After a bloodmeal containing Francisella, adult female An. gambiae and Ae. aegypti retained detectable levels of Francisella DNA for 3 d, but when they took a second bloodmeal, the mammalian host was not infected. This study suggests that although Francisella DNA can be detected in a significant portion of wild-caught mosquitoes, transmission of Francisella is either very inefficient or is species dependent for the Francisella strain or the arthropod vector.

Tularemia is a zoonotic disease caused by the Category A bioterrorism agent Francisella tularensis. In Scandinavia, tularemia transmission by mosquitoes has been widely cited in the literature. We tested >2,500 mosquitoes captured in Alaska and found Francisella DNA in 30% of pooled samples. To examine the potential for transmission of Francisella by mosquitoes, we developed a mosquito model of Francisella infection. Larvae of Anopheles gambiae Giles and Aedes aegypti (L.) readily ingest F. tularensis but do not efficiently transfer infective doses of the bacterium to the pupal or adult stage. After a bloodmeal containing Francisella, adult female An. gambiae and Ae. aegypti retained detectable levels of Francisella DNA for 3 d, but when they took a second bloodmeal, the mammalian host was not infected. This study suggests that although Francisella DNA can be detected in a significant portion of wild-caught mosquitoes, transmission of Francisella is either very inefficient or is species dependent for the Francisella strain or the arthropod vector.

CD4+ Keywords: IgG1 r Immunity r Plasmodium yoelii r T-bet Additional supporting information may be found in the online version of this article at the publisher's web-site

These studies provide a framework to assess the safety of γ-irradiation attenuation and promising targets for genetic deletion to produce whole parasite-based attenuated vaccines.

The inability of neonates to develop CD4+CXCR5+PD-1+ T follicular helper (TFH) cells contributes to their weak vaccine responses. In adult mice, IL-6 promotes TFH-cell expansion by suppressing the expression of IL-2Rβ on TFH cells. Here, we found a totally opposite role for IL-6 in neonatal mice TFH response. Whereas co-injection of neonatal mice with IL-6 and a conjugate polysaccharide vaccine suppressed TFH response by increasing the production of IL-2 and expression of IL-2Rα and IL-2Rβ on TFH cells, immunization of IL-6 knock-out neonatal mice led to improved antibody responses accompanied by expanded TFH cells as well as lower levels of IL-2 and IL-2 receptors on TFH cells. Moreover, CpG containing vaccine improved TFH response in neonates while suppressing the expression of IL-2 receptors on TFH cells, suggesting that CpG protects TFH cells by inhibiting IL-2 activity. These findings unveil age specific differences in IL-6 mediated vaccine responses and highlight the need to consider age related immunobiological attributes in designing vaccines.