of the smooth endoplasmic reticulum, and is the only inducible isoform of HO. The expression of HO-1 occurs at low levels in most tissues under physiological conditions. HO-1 can localize STAT3 Activation in Severe Malaria to distinct subcellular compartments. Inducible HO activity appeared in plasma membrane, cytosol, mitochondria, isolated caveolae and nucleus in cell culture 
models. Early studies indicate that HO-1 in mitochondria and caveolae performs important biological and physiological actions, although the function of HO-1 in caveolae and nucleus is not completely 7 STAT3 Activation in Severe Malaria understood. The nuclear form of HO-1 serves potentially as a Scopoletin transcriptional regulator. Under conditions of hypoxia, hemin or Heme-hemopexin, HO-1 translocates to the nucleus. Nuclear translocation compromises the HO activity, but nuclear localization of HO-1 protein functions to up-regulate genes that promote cytoprotection against oxidative stress. Our data showed that levels of HO-1 were significantly increased in plasma and tissues, the activated HO-1 protein was mostly located in the nucleus, which supports the hypothesis that HO-1 protects against Heme and tissue damage. In CXCL102/2 mice, 21937737 PBA infection caused modest increase in HO-1 mRNA, but not in HO-1 protein, there could be a number of reasons. HO-1 protein may be expressed but at levels below detectable limits, or may be rapidly degraded. As protein expression reflects functional adaption observed in species phenotype, HO-1 in either case probably did not exert the expected protection. Considering the fact that there was no significant difference in free Heme level between CXC102/2 infected mice and non-infected controls, we postulated that HO-1 activation may not be required under this situation. Animal models provide valuable biological information under controlled circumstances. However, different mice strains show variations in susceptibility to rodent malaria, this may reflect qualitative or quantitative differences in host immune response to the parasite and differences in the pathogenicity of sub-strains of murine malaria parasite species. C57BL/6 infected with PBA shares many features similar to human CM. However, lung damage might not be severe enough to cause animal death. This may explain why the pathological manifestation in lung and kidney was modest our study. Our observation of Hb levels being lower in infected wild type mice is consistent with previous studies which showed that P.berghei ANKA infection in C57BL/6 results in anemia. CXCL10 gene deficiency ” prevents decrease in Hb levels. Since the level of free Heme is not increased, it is possible that this may occur through reduction of hemolysis of infected RBC. But the compromised clearance of uninfected RBCs or erythroid response could not be excluded as a possibility. A recent study in Ghanaian patients demonstrated an association between fatal CM and increased serum and cerebrospinal fluid levels of proinflammatory and proapoptotic factors including CXCL10, IL-1ra, sTNFR1, sTNFR2 and sFas and decreased serum and CSF levels of neuroprotective angiogenic growth factors . Further investigation in Indian patients confirmed findings from Ghana, thus indicating STAT3 Activation in Severe Malaria that CXCL10, sTNFR2 and sFas are positively correlated, while angiogenic and anti-apoptotic factors, VEGF is negatively correlated with mortality associated with CM. Studies from a murine CM model also confirmed i