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•An active surveillance through a phased introduction of the Hib vaccine in Japan was studied.•Hib disease incidence decreased significantly after vaccine introduction.•Hif and non-typeable H. influenzae were isolated from a few cases.•Serotype replacement was not observed after the introduction of the Hib vaccine.•Continuous capsular typing and strain identification surveillance is important. Haemophilus influenzae type b (Hib) vaccine was introduced as a voluntary vaccine in December 2008 and was included in the national routine immunization program in April 2013 in Japan. Currently, no nationwide data are available to evaluate the effectiveness of Hib vaccine in Japan. To evaluate the effectiveness of Hib vaccine in Japan, nationwide active population-based surveillance of culture-proven invasive infections caused by H. influenzae in children was performed in 2008–2017 in 10 prefectures in Japan (covering approximately 23% of the total Japanese population). Clinical data were recorded on a standardized case report form. Capsular type and antimicrobial susceptibility of the H. influenzae isolates were examined. The incidence rate ratio (IRR) and its confidence interval (CI) were calculated to compare data from 5 years before and that from after the introduction of the national routine Hib vaccine immunization program. During the 10-year study period, 566 invasive H. influenzae disease cases including 336 meningitis cases were identified. The average number of invasive H. influenzae disease cases among children <5 years of age during 2013–2017 decreased by 93% (IRR: 0.07, 95%CI 0.05–0.10, p < 0.001) compared with those occurring during 2008–2012. Hib strains have not been isolated from invasive H. influenzae disease cases since 2014; however, non-typeable H. influenzae and H. influenzae type f isolates have been noted as causes of invasive H. influenzae diseases among children <5 years in the post-Hib vaccine era. After the governmental subsidization of the Hib vaccine, invasive Hib disease cases decreased dramatically in the study population, as per our surveillance. Continuous surveillance is necessary to monitor the effectiveness of Hib vaccine and for detecting any emerging invasive capsular types.

Ebola Zaire virus is highly pathogenic for humans, with case fatality rates approaching 90% in large outbreaks in Africa. The virus replicates in macrophages and dendritic cells (DCs), suppressing production of type I interferons (IFNs) while inducing the release of large quantities of proinflammatory cytokines. Although the viral VP35 protein has been shown to inhibit IFN responses, the mechanism by which it blocks IFN production has not been fully elucidated. We expressed VP35 from a mouse-adapted variant of Ebola Zaire virus in murine DCs by retroviral gene transfer, and tested for IFN transcription upon Newcastle Disease virus (NDV) infection and toll-like receptor signaling. We found that VP35 inhibited IFN transcription in DCs following these stimuli by disabling the activity of IRF7, a transcription factor required for IFN transcription. By yeast two-hybrid screens and coimmunoprecipitation assays, we found that VP35 interacted with IRF7, Ubc9 and PIAS1. The latter two are the host SUMO E2 enzyme and E3 ligase, respectively. VP35, while not itself a SUMO ligase, increased PIAS1-mediated SUMOylation of IRF7, and repressed Ifn transcription. In contrast, VP35 did not interfere with the activation of NF-kappaB, which is required for induction of many proinflammatory cytokines. Our findings indicate that Ebola Zaire virus exploits the cellular SUMOylation machinery for its advantage and help to explain how the virus overcomes host innate defenses, causing rapidly overwhelming infection to produce a syndrome resembling fulminant septic shock.

Bartonella bacilliformis is the causative agent of Carrion's disease, a neglected illness with mortality rates of 40-85% in the absence of treatment. The lack of a diagnostic technique to overcome misdiagnosis and treat asymptomatic carriers is of note. This study aimed to identify new B. bacilliformis antigenic candidates that could lead to a new diagnostic tool able to be implemented in endemic rural areas. Blood (n = 198) and serum (n = 177) samples were collected in northern Peru. Clinical data were recorded. Specific 16S rRNA amplification by RT-PCR, IFA and ELISA for IgM/IgG with whole cells as antigens was done. Western blot analysis and N-terminal amino acid sequencing detected seroreactive proteins. ELISAs for IgM/IgG for the antigenic candidates were performed. Of the population 33.3% reported at least one symptom compatible with Carrion's disease; 25.4% (IFA), 27.1% (ELISA-IgG), 33.9% (ELISA-IgM) and 38.9% (RT-PCR) of samples were positive. Four proteins were considered potential antigenic candidates, including two new antigenic candidates, succinyl-CoA synthetase subunit α (SCS-α) and succinyl-CoA synthetase subunit β (SCS-β). On Western blot both Pap31 and SCS-α interacted with IgM, while GroEL and SCS-β interacted with IgG. The presence of specific antibodies against the antigenic candidates varied from 34.5% (IgG against SCS-α) to 97.2% (IgM against Pap31). RT-PCR and the high levels of positivity for specific ELISAs demonstrate high levels of B. bacilliformis exposure and asymptomatic carriers among inhabitants. The new antigens identified might be used as a new rapid diagnostic tool to diagnose acute Carrion's disease and identify asymptomatic carriers.

Bartonella bacilliformis is the causal agent of Carrion’s disease, an overlooked illness endemic in the Andean Mountains with Peru being the most affected country. The diagnostic of this illness is a challenge due to the limited resources and the common symptomatology with other infectious diseases. The goal of this study was to identify immunogenic peptides from Pap31 and succinyl-CoA synthetase α (SCS-α) of B. bacilliformis that might be suitable for developing a serologic tool. The immunodominant character of Pap31 and SCS-α was determined by Western blotting and in-silico analysis. Subsequently, 35 peptides were selected for epitope mapping and their immunoreactivity was tested by enzyme-linked immunosorbent assay (ELISA). A total of 30 sera were tested including pre-exposed people with high IgM levels for Pap31/SCS-α (23 sera), patients (2 sera) as well as 5 sera with no reactivity to Pap31/SCS-α. The results indicate that Pap31-8 (187QAIGSAILKGTKDTGT202) and SCS-α-12 (59IFASVAEGKEKTGANA74) are the most immunogenic peptides, with Pap31-8 showing potential to discriminate between B. bacilliformis and the remaining Bartonella spp., and SCS-α-12 differentiating Bartonella spp. from other microorganisms.

Inhibitor of κB kinase ε (IKKε) and TANK binding kinase 1 (TBK1), so-called non-canonical IKKs or IKK-related kinases, are involved in the cellular innate immunity by inducing type I IFNs. Two kinases commonly phosphorylate transcription factors IRF3 and IRF7 in type I IFN production pathway. In contrast to TBK1, underlying mechanisms of IKKε activation and regions required for activation of downstream molecules are poorly understood. In this study, we investigated regions of IKKε required for the activation of type I IFN promoter specially, by focusing on the C-terminal region. To show the functional significance of the IKKε C-terminal region on type I IFN production, we employed various mutant forms of IKKε and compared to corresponding region of TBK1. We identified the specific regions and residues of IKKε involved in the activation of downstream signaling. Interestingly, corresponding region and residues are not required for activation of downstream signaling by TBK1. The results highlight the importance of the C-terminal region in the functional activity of IKKε in innate immune response and also the difference in activation mechanisms between IKKε and the closely related TBK1.

Dengue virus (DENV) infection is the most common mosquito-borne viral disease threatening human health around the world. Type I interferon (IFN) and cytokine production are crucial in the innate immune system. We previously reported that DENV serotype 2 (DENV-2) induced low levels of interferon regulatory factor 3 and NF-κB activation, thus leading to reduced production of IFN-β in the early phase of infection. Here, we determined whether DENV infection not only hampers type I IFN activation but also cytokine production triggered by Toll-like receptor (TLR) signaling. We used quantitative RT-PCR and found that only low levels of IFN-β and inflammatory cytokines such as interleukin 10 (IL-10), IL-12 and tumor necrosis factor α (TNFα) mRNA were detected in DENV-2-infected bone-marrow-derived dendritic cells. Furthermore, DENV-2 infection repressed cytokine production triggered by TLR signaling. To elucidate the molecular mechanisms underlying this suppression event, we measured NF-κB activation by p65 nuclear translocation and luciferase reporter assay and found that NF-κB activation triggered by TLR ligands was blocked by DENV-2 infection. As well, extracellular signal-regulated kinase (ERK) activity was suppressed by DENV-2 infection. To downregulate the host innate immunity, DENV-2 by itself is a weak inducer of type I IFN and cytokines, furthermore DENV-2 can also block the TLR-triggered ERK-NF-κB activation and cytokine production.

Bartonella quintana is a gram-negative bacterium causing trench fever, an illness historically acquired by soldiers during World War I. More recently, outbreaks of trench fever have been reported in those experiencing homelessness in the United States, France, Russia, and Tokyo, as well as in children in Nepal and persons in Ethiopia. Reports of B. quintana infection outside of Tokyo are rare in Japan. The aim of this study was to examine body lice and blood obtained from people staying in shelters in Osaka (2009–2010) for B. quintana via polymerase chain reaction and enzyme-linked immunosorbent assays. Day laborers were defined as homeless individuals and shelter residents in this study. We detected genes of B. quintana in body lice by PCR and antibodies against B. quintana. The positive rate of B. quintana genes was 6/10 (60%) in body lice and the seroprevalence (IgG) of B. quintana was 4/10 (40%).This demonstrates that trench fever was endemic in people staying in shelters in Osaka in 2009–2010.

Bartonella quintana is a gram-negative bacterium causing trench fever, an illness historically acquired by soldiers during World War I. More recently, outbreaks of trench fever have been reported in those experiencing home-lessness in the United States, France, Russia, and Tokyo, as well as in children in Nepal and persons in Ethiopia. Reports of B. quintana infection outside of Tokyo are rare in Japan. The aim of this study was to examine body lice and blood obtained from people staying in shelters in Osaka (2009-2010) for B. quintana via polymerase chain reaction and enzyme-linked immunosorbent assays. Day laborers were defined as homeless individuals and shelter residents in this study. We detected genes of B. quintana in body lice by PCR and antibodies against B. quintana. The positive rate of B. quintana genes was 6/10 (60%) in body lice and the seroprevalence (IgG) of B. quintanawas 4/10 (40%). This demonstrates that trench fever was endemic in people staying in shelters in Osaka in 2009-2010.

Hydroxychloroquine (HCQ) is an antimalarial drug also used in treating autoimmune diseases. Its antiviral activity was demonstrated in restricting HIV infection in vitro; however, the clinical implications remain controversial. Infection with dengue virus (DENV) is a global public health problem, and we lack an antiviral drug for DENV. Here, we evaluated the anti-DENV potential of treatment with HCQ. Immunofluorescence assays demonstrated that HCQ could inhibit DENV serotype 1–4 infection in vitro. RT-qPCR analysis of HCQ-treated cells showed induced expression of interferon (IFN)-related antiviral proteins and certain inflammatory cytokines. Mechanistic study suggested that HCQ activated the innate immune signaling pathways of IFN-β, AP-1, and NFκB. Knocking down mitochondrial antiviral signaling protein (MAVS), inhibiting TANK binding kinase 1 (TBK1)/inhibitor-κB kinase ɛ (IKKɛ), and blocking type I IFN receptor reduced the efficiency of HCQ against DENV-2 infection. Furthermore, HCQ significantly induced cellular production of reactive oxygen species (ROS), which was involved in the host defense system. Suppression of ROS production attenuated the innate immune activation and anti-DENV-2 effect of HCQ. In summary, HCQ triggers the host defense machinery by inducing ROS- and MAVS-mediated innate immune activation against DENV infection and may be a candidate drug for DENV infection.