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Lung resident memory CD8 T cells (TRM) are critical for protection against respiratory viruses, but the cellular interactions required for their development are poorly understood. Herein we describe the necessity of classical monocytes for the establishment of lung TRM following influenza infection. We find that, during the initial appearance of lung TRM, monocytes and dendritic cells are the most numerous influenza antigen-bearing APCs in the lung. Surprisingly, depletion of DCs after initial T cell priming did not impact lung TRM development or maintenance. In contrast, a monocyte deficient pulmonary environment in CCR2−/− mice results in significantly less lung TRM following influenza infection, despite no defect in the antiviral effector response or in the peripheral memory pool. Imaging shows direct interaction of antigen-specific T cells with antigen-bearing monocytes in the lung, and pulmonary classical monocytes from the lungs of influenza infected mice are sufficient to drive differentiation of T cells in vitro. These data describe a novel role for pulmonary monocytes in mediating lung TRM development through direct interaction with T cells in the lung.

The menstrual cycle influences the risk of acquiring sexually transmitted infections (STIs), including those caused by the pathogen Chlamydia trachomatis ( C. trachomatis ). However, the underlying immune contributions are poorly defined. A mouse model simulating the repetitive immune-mediated process of menstruation could provide valuable insights into tissue-specific determinants of protection against chlamydial infection within the cervicovaginal and uterine mucosae of the female reproductive tract (FRT). Here, we used the pseudopregnancy approach for inducing menstruation in naïve C57Bl/6 mice and performed vaginal challenge with Chlamydia muridarum ( C. muridarum ) over the course of decidualization, endometrial tissue remodeling, and menstruation. This strategy identified that a time point over pseudopregnancy corresponding to the late luteal phase of the menstrual cycle correlated with reduced bacterial burden. By evaluating the early infection site following challenge at this time point, we found that a greater abundance of NK cell populations and proinflammatory signaling, including IFNγ, were strongly correlated with protection. FRT immune profiling in uninfected mice over pseudopregnancy or in pig-tailed macaques over the menstrual cycle identified periodic NK cell infiltration into the cervicovaginal tissues and luminal surface occurring over a similar time frame. Notably, these cell populations were transcriptionally distinct and enriched for programs associated with NK cell effector functions. Depletion of FRT NK cells during the late luteal phase time frame resulted in a loss of protection, enabling productive infection following C. muridarum challenge. This study shows that the pseudopregnancy murine menstruation model recapitulates dynamic changes occurring in mucosal immune states throughout the FRT as a result of endometrial remodeling and identifies NK cell localization at the FRT barrier site of pathogen exposure as essential for immune protection against primary C. muridarum infection.

Tissue-resident memory T cells (T RM cells) are critical for cellular immunity to respiratory pathogens and reside in both the airways and the interstitium. In the present study, we found that the airway environment drove transcriptional and epigenetic changes that specifically regulated the cytolytic functions of airway T RM cells and promoted apoptosis due to amino acid starvation and activation of the integrated stress response. Comparison of airway T RM cells and splenic effector-memory T cells transferred into the airways indicated that the environment was necessary to activate these pathways, but did not induce T RM cell lineage reprogramming. Importantly, activation of the integrated stress response was reversed in airway T RM cells placed in a nutrient-rich environment. Our data defined the genetic programs of distinct lung T RM cell populations and show that local environmental cues altered airway T RM cells to limit cytolytic function and promote cell death, which ultimately leads to fewer T RM cells in the lung. Kohlmeier and colleagues showed that the airway environment drove transcriptional and epigenetic changes that regulated the cytolytic functions of airway T RM cells and promoted their apoptosis due to amino acid starvation and activation of the integrated stress response.

The increasing dengue burden and epidemic severity worldwide have highlighted the need to improve surveillance. In non-endemic areas such as Taiwan, where outbreaks start mostly with imported cases from Southeast Asia, a closer examination of surveillance dynamics to detect cases early is necessary. To evaluate problems with dengue surveillance and investigate the involvement of different factors at various epidemic stages, we investigated 632 laboratory-confirmed indigenous dengue cases in Kaohsiung City, Taiwan during 2009-2010. The estimated sensitivity of clinical surveillance was 82.4% (521/632). Initially, the modified serological surveillance (targeting only the contacts of laboratory-confirmed dengue cases) identified clinically unrecognized afebrile cases in younger patients who visited private clinics and accounted for 30.4% (35/115) of the early-stage cases. Multivariate regression indicated that hospital/medical center visits [Adjusted Odds Ratio (aOR): 11.6, 95% confidence interval (CI): 6.3-21.4], middle epidemic stage [aOR: 2.4 (1.2-4.7)], fever [aOR: 2.3 (2.3-12.9)], and musculo-articular pain [aOR: 1.9 (1.05-3.3)] were significantly associated with clinical reporting. However, cases with pruritus/rash [aOR: 0.47 (0.26-0.83)] and diarrhea [aOR: 0.47 (0.26-0.85)] were underreported. In conclusion, multiple factors contributed to dengue surveillance problems. To prevent a large-scale epidemic and minimize severe dengue cases, there is a need for integrated surveillance incorporating entomological, clinical, serological, and virological surveillance systems to detect early cases, followed by immediate prevention and control measures and continuous evaluation to ensure effectiveness. This effort will be particularly important for an arbovirus, such as Zika virus, with a high asymptomatic infection ratio. For dengue- non-endemic countries, we recommend serological surveillance be implemented in areas with high Aedes mosquito indices or many breeding sites. Syndromic surveillance, spatial analysis and monitoring changes in epidemiological characteristics using a geographical information system, as well as epidemic prediction models involving epidemiological, meteorological and environmental variables will be helpful for early risk communication to increase awareness.

The 2009 influenza pandemic provided an opportunity to observe dynamic changes of the hemagglutinin (HA) and neuraminidase (NA) of pH1N1 strains that spread in two metropolitan areas--Taipei and Kaohsiung. We observed cumulative increases of amino acid substitutions of both HA and NA that were higher in the post-peak than in the pre-peak period of the epidemic. About 14.94% and 3.44% of 174 isolates had one and two amino acids changes, respective, in the four antigenic sites. One unique adaptive mutation of HA2 (E374K) was first detected three weeks before the epidemic peak. This mutation evolved through the epidemic, and finally emerged as the major circulated strain, with significantly higher frequency in the post-peak period than in the pre-peak (64.65% vs 9.28%, p<0.0001). E374K persisted until ten months post-nationwide vaccination without further antigenic changes (e.g. prior to the highest selective pressure). In public health measures, the epidemic peaked at seven weeks after oseltamivir treatment was initiated. The emerging E374K mutants spread before the first peak of school class suspension, extended their survival in high-density population areas before vaccination, dominated in the second wave of class suspension, and were fixed as herd immunity developed. The tempo-spatial spreading of E374K mutants was more concentrated during the post-peak (p = 0.000004) in seven districts with higher spatial clusters (p<0.001). This is the first study examining viral changes during the naïve phase of a pandemic of influenza through integrated virological/serological/clinical surveillance, tempo-spatial analysis, and intervention policies. The vaccination increased the percentage of E374K mutants (22.86% vs 72.34%, p<0.001) and significantly elevated the frequency of mutations in Sa antigenic site (2.36% vs 23.40%, p<0.001). Future pre-vaccination public health efforts should monitor amino acids of HA and NA of pandemic influenza viruses isolated at exponential and peak phases in areas with high cluster cases.

[This corrects the article DOI: 10.1371/journal.pone.0160230.].

Lung resident memory CD8 T cells (T ) are critical for protection against respiratory viruses, but the cellular interactions required for their development are poorly understood. Herein we describe the necessity of classical monocytes for the establishment of lung T following influenza infection. We find that, during the initial appearance of lung T , monocytes and dendritic cells are the most numerous influenza antigen-bearing APCs in the lung. Surprisingly, depletion of DCs after initial T cell priming did not impact lung T development or maintenance. In contrast, a monocyte deficient pulmonary environment in CCR2 mice results in significantly less lung T following influenza infection, despite no defect in the antiviral effector response or in the peripheral memory pool. Imaging shows direct interaction of antigen-specific T cells with antigen-bearing monocytes in the lung, and pulmonary classical monocytes from the lungs of influenza infected mice are sufficient to drive differentiation of T cells in vitro. These data describe a novel role for pulmonary monocytes in mediating lung T development through direct interaction with T cells in the lung.

School children may transmit pathogens with cluster cases occurring on campuses and in families. In response to the 2009 influenza A (H1N1) pandemic, Taipei City Government officials developed a School-based Infectious Disease Syndromic Surveillance System (SID-SSS). Teachers and nurses from preschools to universities in all 12 districts within Taipei are required to daily report cases of symptomatic children or sick leave requests through the SID-SSS. The pre-diagnosis at schools is submitted firstly as common pediatric disease syndrome-groups and re-submitted after confirmation by physicians. We retrieved these data from January 2010 to August 2011 for spatio-temporal analysis and evaluated the temporal trends with cases obtained from both the Emergency Department-based Syndromic Surveillance System (ED-SSS) and the Longitudinal Health Insurance Database 2005 (LHID2005). Through the SID-SSS, enterovirus-like illness (EVI) and influenza-like illness (ILI) were the two most reported syndrome groups (77.6% and 15.8% among a total of 19,334 cases, respectively). The pre-diagnosis judgments made by school teachers and nurses showed high consistency with physicians' clinical diagnoses for EVI (97.8%) and ILI (98.9%). Most importantly, the SID-SSS had better timeliness with earlier peaks of EVI and ILI than those in the ED-SSS. Furthermore, both of the syndrome groups in these two surveillance systems had the best correlation reaching 0.98 and 0.95, respectively (p<0.01). Spatio-temporal analysis observed the patterns of EVI and ILI both diffuse from the northern suburban districts to central Taipei, with ILI spreading faster. This novel system can identify early suspected cases of two important pediatric infections occurring at schools, and clusters from schools/families. It was also cost-effective (95.5% of the operation cost reduced and 59.7% processing time saved). The timely surveillance of mild EVI and ILI cases integrated with spatial analysis may help public health decision-makers with where to target for enhancing surveillance and prevention measures to minimize severe cases.

The largest epidemic of avian influenza (AI) in history attacked poultry and wild birds throughout Taiwan starting January 6, 2015. This study analyzed surveillance results, epidemiologic characteristics, and viral sequences by using government-released information, with the intention to provide recommendations to minimize future pandemic influenza. The H5 clade 2.3.4.4 highly pathogenic AI viruses (HPAIVs) had not been detected in Taiwan before 2015. During this epidemic, four types of etiologic agents were identified: the three novel subtypes H5N2, H5N8, and H5N3 clade 2.3.4.4 HPAIVs and one endemic chicken H5N2 subtype (Mexican-like lineage) of low pathogenic AI viruses. Cocirculation of mixed subtypes also occurred, with H5N2 clade 2.3.4.4 HPAIVs accompanied by the H5N8 and H5N3 subtypes or old H5N2 viruses in the same farm. More than 90% of domestic geese died from this AI epidemic; geese were affected the most at the early outbreaks. The epidemic peaked in mid-January for all three novel H5 subtypes. Spatial epidemiology found that most affected areas were located in southwestern coastal areas. In terrestrial poultry (mostly chickens), different geographic distributions of AI virus subtypes were detected, with hot spots of H5N2 clade 2.3.4.4 vs. past-endemic old H5N2 viruses in Changhwa (P = 0.03) and Yunlin (P = 0.007) counties, respectively, of central Taiwan. Phylogenetic and sequence analyses of all the early 10 Taiwan H5 clade 2.3.4.4 isolates covering the three subtypes showed that they were very different from the HA of the past local H5 viruses from domestic ducks (75%–80%) and chickens (70%–75%). However, they had the highest sequence identity percentages (99.53%–100%), with the HA of A/crane/Kagoshima/KU13/2014(H5N8) isolated on December 7, 2014, in Japan being higher than those of recent American and Korean H5 HPAIVs [A/Northern pintail/Washington/40964/2014 (H5N2) and A/gyrfalcon/Washington/41088-6/2014 (H5N8): 99.02%–99.54% and A/Baikal teal/Korea/Donglim3/2014 (H5N8): 98.61%–99.08%], implying a likely common ancestor of these H5 clade 2.3.4.4 viruses. The multiple subtypes of H5 clade 2.3.4.4 HPAIVs imply high viral reassortment. We recommend establishing an integrated surveillance system, involving clinical, virologic, and serologic surveillance in poultry and wild birds, swine and other mammals prevalent on multiple-animal mixed-type traditional farms, and high-risk human populations, as a crucially important step to minimize future pandemic influenza.

The menstrual cycle influences the risk of acquiring sexually transmitted infections (STIs), including ( ), although the underlying immune contributions are poorly defined. A mouse model simulating the immune-mediated process of menstruation could provide valuable insights into tissue-specific determinants of protection against chlamydial infection within the cervicovaginal and uterine mucosae comprising the female reproductive tract (FRT). Here, we used the pseudopregnancy approach in naïve C57Bl/6 mice and performed vaginal challenge with ( ) at decidualization, endometrial tissue remodeling, or uterine repair. This strategy identified that the time frame comprising uterine repair correlated with robust infection and greater bacterial burden as compared with mice on hormonal contraception, while challenges during endometrial remodeling were least likely to result in a productive infection. By comparing the infection site at early time points following chlamydial challenge, we found that a greater abundance of innate effector populations and proinflammatory signaling, including IFNγ correlated with protection. FRT immune profiling in uninfected mice over pseudopregnancy or in pig-tailed macaques over the menstrual cycle identified NK cell infiltration into the cervicovaginal tissues and lumen over the course of endometrial remodeling. Notably, NK cell depletion over this time frame reversed protection, with mice now productively infected with following challenge. This study shows that the pseudopregnancy murine menstruation model recapitulates immune changes in the FRT as a result of endometrial remodeling and identifies NK cell localization at the FRT as essential for immune protection against primary infection.