Th e observation that lack of RAGE is of benefi t in one pneumonia model and detrimental in another, clearly adds to the notion that the way in which RAGE mediates host defense against diff erent pathogens relies on distinct mechanisms. It would be highly interesting to evaluate whether RAGE can directly bind to, become activated, and mount a fi rst immune reaction after ligation with specifi c PAMPs. Furthermore, RAGE-mediated eff ects on other fi rst-line defense mechanisms, such as chemotaxis, killing, phagocytosis and respiratory burst could depend on the pathogen. As such, targeting RAGE may be ineff ective or even harmful in some infectious conditions. Th erefore, more studies are necessary to justify clinical trials targeting RAGE in patients with severe infections. In this respect one could think of research on RAGE inhibition in pneumococcal and infl uenza A viral pneumonia. Additionally, experiments in which RAGE targeting is delayed until after bacterial/viral infection and combined with antibiotic/antiviral therapy should be considered. Moreover, more studies need to be conducted on the role of RAGE in critical organ derangements involved in the pathogenesis of severe infection, including activation of the coagulation system and the complement system. RAGE remains a potential yet promising therapeutic target that awaits further research. Metagenomic Analysis of Fever, Thrombocytopenia and Leukopenia Syndrome (FTLS) in Henan Province, China: Discovery of a New Bunyavirus Since 2007, many cases of fever, thrombocytopenia and leukopenia syndrome (FTLS) have emerged in Henan Province, China. Patient reports of tick bites suggested that infection could contribute to FTLS. Many tick-transmitted microbial pathogens were tested for by PCR/RT-PCR and/or indirect immunofluorescence assay (IFA). However, only 8% (24/285) of samples collected from 2007 to 2010 tested positive for human granulocytic anaplasmosis (HGA), suggesting that other pathogens could be involved. Here, we used an unbiased metagenomic approach to screen and survey for microbes possibly associated with FTLS. BLASTx analysis of deduced protein sequences revealed that a novel bunyavirus (36% identity to Tehran virus, accession: HQ412604) was present only in sera from FTLS patients. A phylogenetic analysis further showed that, although closely related to Uukuniemi virus of the Phlebovirus genus, this virus was distinct. The candidate virus was examined for association with FTLS among samples collected from Henan province during 2007–2010. RT-PCR, viral cultures, and a seroepidemiologic survey were undertaken. RT-PCR results showed that 223 of 285 (78.24%) acute-phase serum samples contained viral RNA. Of 95 patients for whom paired acute and convalescent sera were available, 73 had serologic evidence of infection, with 52 seroconversions and 21 exhibiting a 4-fold increase in antibody titer to the virus. The new virus was isolated from patient acute-phase serum samples and named Henan Fever Virus (HNF virus). Whole-genome sequencing confirmed that the virus was a novel bunyavirus with genetic similarity to known bunyaviruses, and was most closely related to the Uukuniemi virus (34%, 24%, and 29% of maximum identity, respectively, for segment L, M, S at maximum query coverage). After the release of the GenBank sequences of SFTSV, we found that they were nearly identical (>99% identity). These results show that the novel bunyavirus (HNF virus) is strongly correlated with FTLS. In May 2007, a county hospital in Xinyang City, Henan Province treated three patients with fever, abdominal pain, bloating, nausea, vomiting, gastrointestinal bleeding, and elevated aminotransferases. The local hospital diagnosed the disease as acute gastroenteritis. A family member of one patient reported the disease to the Henan Center for Disease Control and Prevention (CDC), which sent a team to investigate. The investigation revealed that the disease had the following characteristics: (1) acute onset with fever; (2) low white blood cell and platelet counts; (3) high levels of alanine and aspartate transaminases; (4) positive urine protein. On the basis of these features, the Henan CDC excluded the possibility of gastrointestinal disorders. In order to identify the disease etiology, the Henan CDC team used the above clinical characteristics as the case definition to search for similar cases in local hospitals in this and neighboring counties, while establishing a disease surveillance system that required all medical institutions to report cases that met the above case definition. Altogether, 79 cases were found in 2007 in Henan, with 10 fatalities (case fatality rate, 12.7%). All patients were farmers and resided in mountainous or hilly villages, and many had reported tick bites 7-9 days before illness, further suggesting an infectious etiology. In recent years, patients with similar clinical symptoms were reported with human granulocytic anaplasmosis (HGA; Anaplasma phagocytophilum) in neighboring Anhui province [1] . In 2005, there was an epidemic of Tsutsugamushi (scrub typhus/ Orientia tsutsugamushi) in this area [2] . Clinical investigations, epidemiological analyses, and laboratory testing prompted consideration of rickettsial diseases as possible causes, including HGA, human monocytic ehrlichiosis (HME; Ehrlichia chaffeensis), and Tsutsugamushi disease. Specific methods such as polymerase chain reaction (PCR) and immunofluorescence assays (IFAs) for these pathogens were then used to determine if these cases were attributable to HGA or HME [3, 4] . However, only 18 of 79 (22.7%) patients were positive for A. phagocytophilum based on serology and DNA testing. Thus, the disease was initially considered at least partly caused by A. phagocytophilum, and cases were provisionally diagnosed as suspected HGA based on clinical and epidemiological data [1] [2] [3] [5] [6] [7] . In the 3 years since 2007, 206 suspected cases have been discovered in Henan, but there was only a very low positive rate of A. phagocytophilum confirmation (6 of 206 patients) and no pathogen was isolated. Similar cases were also reported in the mountainous and hilly areas of nearby Shandong, Jiangsu, Hubei and Anhui provinces, indicating that the disease already existed for some time and was widely distributed [7] . We decided to address the possible causative pathogen underlying this infection.