Interleukin 21 Drives a Hypermetabolic State and CD4+ T-Cell-Associated Pathogenicity in Chronic Intestinal Inflammation.

BACKGROUND & AIMS: Incapacitated regulatory T cells (Tregs) contribute to immune-mediated diseases. Inflammatory Tregs are evident during human inflammatory bowel disease; however, mechanisms driving the development of these cells and their function are not well understood. Therefore, we investigated the role of cellular metabolism in Tregs relevant to gut homeostasis. METHODS: Using human Tregs, we performed mitochondrial ultrastructural studies via electron microscopy and confocal imaging, biochemical and protein analyses using proximity ligation assay, immunoblotting, mass cytometry and fluorescence-activated cell sorting, metabolomics, gene expression analysis, and real-time metabolic profiling utilizing the Seahorse XF analyzer. We used a Crohn's disease single-cell RNA sequencing dataset to infer the therapeutic relevance of targeting metabolic pathways in inflammatory Tregs. We examined the superior functionality of genetically modified Tregs in CD4+ T-cell-induced murine colitis models. RESULTS: Mitochondria-endoplasmic reticulum appositions, known to mediate pyruvate entry into mitochondria via voltage-dependent anion channel 1 (VDAC1), are abundant in Tregs. VDAC1 inhibition perturbed pyruvate metabolism, eliciting sensitization to other inflammatory signals reversible by membrane-permeable methyl pyruvate supplementation. Notably, interleukin (IL) 21 diminished mitochondria-endoplasmic reticulum appositions, resulting in enhanced enzymatic function of glycogen synthase kinase 3 ß, a putative negative regulator of VDAC1, and a hypermetabolic state that amplified Treg inflammatory response. Methyl pyruvate and glycogen synthase kinase 3 ß pharmacologic inhibitor (LY2090314) reversed IL21-induced metabolic rewiring and inflammatory state. Moreover, IL21-induced metabolic genes in Tregs in vitro were enriched in human Crohn's disease intestinal Tregs. Adoptively transferred Il21r-/- Tregs efficiently rescued murine colitis in contrast to wild-type Tregs. CONCLUSIONS: IL21 triggers metabolic dysfunction associated with Treg inflammatory response. Inhibiting IL21-induced metabolism in Tregs may mitigate CD4+ T-cell-driven chronic intestinal inflammation.

The burden and severity of illness due to 2009 pandemic influenza A (H1N1) in a large US city during the late summer and early fall of 2009.

In estimates of illness severity from the spring wave of the 2009 influenza A (H1N1) pandemic, reported case fatality proportions were less than 0.05%. In prior pandemics, subsequent waves of illness were associated with higher mortality. The authors evaluated the burden of the pandemic H1N1 (pH1N1) outbreak in metropolitan Atlanta, Georgia, in the fall of 2009, when increased influenza activity heralded the second wave of the pandemic in the United States. Using data from a community survey, existing surveillance systems, public health laboratories, and local hospitals, they estimated numbers of pH1N1-associated illnesses, emergency department (ED) visits, hospitalizations, intensive care unit (ICU) admissions, and deaths occurring in metropolitan Atlanta during the period August 16, 2009-September 26, 2009. The authors estimated 132,140 pediatric and 132,110 adult symptomatic cases of pH1N1 in metropolitan Atlanta during the investigation time frame. Among children, these cases were associated with 4,560 ED visits, 190 hospitalizations, 51 ICU admissions, and 4 deaths. Among adults, they were associated with 1,130 ED visits, 590 hospitalizations, 140 ICU admissions, and 63 deaths. The combined symptomatic case hospitalization proportion, case ICU admission proportion, and case fatality proportion were 0.281%, 0.069%, and 0.024%, respectively. Influenza burden can be estimated using existing data and local surveys. The increased severity reported for subsequent waves in past pandemics was not evident in this investigation. Nevertheless, the second pH1N1 pandemic wave led to substantial numbers of ED visits, hospitalizations, and deaths in metropolitan Atlanta.

Preliminary results of 2009 pandemic influenza surveillance in the United States using the Aggregate Hospitalization and Death Reporting Activity.

BACKGROUND: To augment established influenza surveillance systems in the United States, the Centers for Disease Control and Prevention and the Council of State and Territorial Epidemiologists implemented the Aggregate Hospitalization and Death Reporting Activity (AHDRA) in August 2009. The AHDRA was designed to meet increased demands for timely and detailed information describing illness severity during the 2009 H1N1 influenza A (pH1N1) pandemic response. OBJECTIVES: We describe the implementation of AHDRA and provide preliminary results from this new surveillance activity. METHODS: All 50 US states were asked to report influenza-associated hospitalizations and deaths to AHDRA each week using either a laboratory-confirmed or syndromic surveillance definition. Aggregate counts were used to calculate age-specific weekly and cumulative rates per 100,000, and laboratory-confirmed reports were used to estimate the age distribution of pH1N1 influenza-associated hospitalizations and deaths. RESULTS: From August 30, 2009, through April 6, 2010, AHDRA identified 41,689 laboratory-confirmed influenza-associated hospitalizations and 2096 laboratory-confirmed influenza-associated deaths. Aggregate Hospitalization and Death Reporting Activity rates peaked earlier than hospitalization and death rates seen in previous influenza seasons with other surveillance systems, and the age distribution of cases revealed a tendency for hospitalizations and deaths to occur in persons <65 years for age. CONCLUSIONS: Aggregate Hospitalization and Death Reporting Activity laboratory-confirmed reports provided important information during the 2009 pandemic response. Aggregate Hospitalization and Death Reporting Activity syndromic reports were marked by low representativeness and specificity and were therefore less useful. The AHDRA was implemented quickly and may be a useful surveillance system to monitor severe illness during future influenza pandemics.

Estimating the burden of 2009 pandemic influenza A (H1N1) in the United States (April 2009-April 2010).

To calculate the burden of 2009 pandemic influenza A (pH1N1) in the United States, we extrapolated from the Centers for Disease Control and Prevention's Emerging Infections Program laboratory-confirmed hospitalizations across the entire United States, and then corrected for underreporting. From 12 April 2009 to 10 April 2010, we estimate that approximately 60.8 million cases (range: 43.3-89.3 million), 274,304 hospitalizations (195,086-402,719), and 12,469 deaths (8868-18,306) occurred in the United States due to pH1N1. Eighty-seven percent of deaths occurred in those under 65 years of age with children and working adults having risks of hospitalization and death 4 to 7 times and 8 to 12 times greater, respectively, than estimates of impact due to seasonal influenza covering the years 1976-2001. In our study, adults 65 years of age or older were found to have rates of hospitalization and death that were up to 75% and 81%, respectively, lower than seasonal influenza. These results confirm the necessity of a concerted public health response to pH1N1.

H1N1 2009 influenza virus infection during pregnancy in the USA.

BACKGROUND: Pandemic H1N1 2009 influenza virus has been identified as the cause of a widespread outbreak of febrile respiratory infection in the USA and worldwide. We summarised cases of infection with pandemic H1N1 virus in pregnant women identified in the USA during the first month of the present outbreak, and deaths associated with this virus during the first 2 months of the outbreak. METHODS: After initial reports of infection in pregnant women, the US Centers for Disease Control and Prevention (CDC) began systematically collecting additional information about cases and deaths in pregnant women in the USA with pandemic H1N1 virus infection as part of enhanced surveillance. A confirmed case was defined as an acute respiratory illness with laboratory-confirmed pandemic H1N1 virus infection by real-time reverse-transcriptase PCR or viral culture; a probable case was defined as a person with an acute febrile respiratory illness who was positive for influenza A, but negative for H1 and H3. We used population estimates derived from the 2007 census data to calculate rates of admission to hospital and illness. FINDINGS: From April 15 to May 18, 2009, 34 confirmed or probable cases of pandemic H1N1 in pregnant women were reported to CDC from 13 states. 11 (32%) women were admitted to hospital. The estimated rate of admission for pandemic H1N1 influenza virus infection in pregnant women during the first month of the outbreak was higher than it was in the general population (0.32 per 100 000 pregnant women, 95% CI 0.13-0.52 vs 0.076 per 100 000 population at risk, 95% CI 0.07-0.09). Between April 15 and June 16, 2009, six deaths in pregnant women were reported to the CDC; all were in women who had developed pneumonia and subsequent acute respiratory distress syndrome requiring mechanical ventilation. INTERPRETATION: Pregnant women might be at increased risk for complications from pandemic H1N1 virus infection. These data lend support to the present recommendation to promptly treat pregnant women with H1N1 influenza virus infection with anti-influenza drugs. FUNDING: US CDC.