Human Desmoglein-2 and Human CD46 Mediate Human Adenovirus Type 55 Infection, but Human Desmoglein-2 Plays the Major Roles.

Human adenovirus type 55 (HAdV55) represents an emerging respiratory pathogen and causes severe pneumonia with high fatality in humans. The cellular receptors, which are essential for understanding the infection and pathogenesis of HAdV55, remain unclear. In this study, we found that HAdV55 binding and infection were sharply reduced by disrupting the interaction of viral fiber protein with human desmoglein-2 (hDSG2) but only slightly reduced by disrupting the interaction of viral fiber protein with human CD46 (hCD46). Loss-of-function studies using soluble receptors, blocking antibodies, RNA interference, and gene knockout demonstrated that hDSG2 predominantly mediated HAdV55 infection. Nonpermissive rodent cells became susceptible to HAdV55 infection when hDSG2 or hCD46 was expressed, but hDSG2 mediated more efficient HAd55 infection than hCD46. We generated two transgenic mouse lines that constitutively express either hDSG2 or hCD46. Although nontransgenic mice were resistant to HAdV55 infection, infection with HAdV55 was significantly increased in hDSG2+/+ mice but was much less increased in hCD46+/+ mice. Our findings demonstrate that both hDSG2 and hCD46 are able to mediate HAdV55 infection but hDSG2 plays the major roles. The hDSG2 transgenic mouse can be used as a rodent model for evaluation of HAdV55 vaccine and therapeutics.IMPORTANCE Human adenovirus type 55 (HAdV55) has recently emerged as a highly virulent respiratory pathogen and has been linked to severe and even fatal pneumonia in immunocompetent adults. However, the cellular receptors mediating the entry of HAdV55 into host cells remain unclear, which hinders the establishment of HAdV55-infected animal models and the development of antiviral approaches. In this study, we demonstrated that human desmoglein-2 (hDSG2) plays the major roles during HAdV55 infection. Human CD46 (hCD46) could also mediate the infection of HAdV55, but the efficiency was much lower than for hDSG2. We generated two transgenic mouse lines that express either hDSG2 or hCD46, both of which enabled HAd55 infection in otherwise nontransgenic mice. hDSG2 transgenic mice enabled more efficient HAdV55 infection than hCD46 transgenic mice. Our study adds to our understanding of HAdV55 infection and provides an animal model for evaluating HAdV55 vaccines and therapeutics.

Incorporation of NS1 and prM/M are important to confer effective protection of adenovirus-vectored Zika virus vaccine carrying E protein.

Current design of Zika virus (ZIKV) vaccine mainly considered envelope (E) as the major target antigen. Non-structural protein NS1 was seldom considered. Herein, we generated three adenovirus-vectored vaccines carrying E (Ad2-E), or premembrane/membrane (prM/M) with E (Ad2-prME), or NS1 in addition to prM/M with E (Ad2-prME-NS1). Ad2-prME induced higher neutralizing antibody response to ZIKV than Ad2-E, suggesting prM/M is important for the folding of immunogenic E. Most intriguingly, Ad2-prME-NS1 elicited the best viral inhibition when the immune sera were added to ZIKV-infected cells. In ZIKV-challenged neonatal mice born to maternally immunized dams, Ad2-prME-NS1 conferred the best protection in preventing weight loss, neurological disorders, and viral replication. Ad2-prME also conferred significant protection but was less effective than Ad2-prME-NS1, whereas Ad2-E only alleviated neurological symptoms but did not inhibit viral replication. Our study suggested that NS1 should be considered in the design of ZIKV vaccine in addition to prM/M and E.

Hexon and fiber of adenovirus type 14 and 55 are major targets of neutralizing antibody but only fiber-specific antibody contributes to cross-neutralizing activity.

Re-emerging human adenoviruses type 14 (HAdV14) and 55 (HAdV55) represent two highly virulent adenoviruses. The neutralizing antibody (nAb) responses elicited by infection or immunization remain largely unknown. Herein, we generated hexon-chimeric HAdV14 viruses harboring each single or entire hexon hyper-variable-regions (HVR) from HAdV55, and determined the neutralizing epitopes of human and mouse nAbs. In human sera, hexon-targeting nAbs are type-specific and mainly recognize HVR2, 5, and 7. Fiber-targeting nAbs are only detectable in sera cross-neutralizing HAdV14 and HAdV55 and contribute substantially to cross-neutralization. Penton-binding antibodies, however, show no significant neutralizing activities. In mice immunized with HAdV14 or HAdV55, a single immunization mainly elicited hexon-specific nAbs, which recognized HAdV14 HVR1, 2, and 7 and HAdV55 HVR1 and 2, respectively. After a booster immunization, cross-neutralizing fiber-specific nAbs became detectable. These results indicated that hexon elicits type-specific nAbs whereas fiber induces cross-neutralizing nAbs to HAdV14 and HAdV55, which are of significance in vaccine development.

Urinary bisphenol A concentration and the risk of central obesity in Chinese adults: A prospective study.

BACKGROUND: Bisphenol A (BPA) exposure has been associated with diabetes and related metabolic disorders, such as obesity, but studies of the association of urinary BPA concentrations with central obesity risk are limited. The aim of this study was to prospectively investigate the association between urinary BPA and incident central obesity in a Chinese population aged ≥40 years. METHODS: The study followed 888 participants from Shanghai, China, who did not have central obesity at baseline (in 2009) for 4 years. Concentrations of BPA were measured in baseline morning spot urine samples. Central obesity was defined as waist circumference ≥90 cm in men and ≥80 cm in women. RESULTS: During a mean follow-up of 4 years, 124 (14.0%) participants developed central obesity. Each 1-unit increase in log [BPA] was positively associated with a 2.30-fold risk of incident central obesity (95% confidence interval [CI] 1.39-3.78; P < 0.001) after adjustment for confounders. Compared with the lowest tertile of urinary BPA concentration, Tertiles 2 and 3 were associated with a higher risk of incident central obesity (odds ratios 1.73 [95% CI 1.04-2.88] and 1.81 [95% CI 1.08-3.05], respectively). Stratified analysis showed significant associations of BPA with incident central obesity in women and individuals <60 years of age, with normal weight, non-smokers, non-drinkers, or non-hypertensives. CONCLUSIONS: The results indicate that higher urinary BPA concentrations may be associated with a greater risk of incident central obesity in Chinese adults. The study emphasizes the effects of BPA exposure on metabolic risk from a public health perspective.

Type 2 Diabetes, Diabetes Genetic Score and Risk of Decreased Renal Function and Albuminuria: A Mendelian Randomization Study.

BACKGROUND: Type 2 diabetes (T2D) is a risk factor for dysregulation of glomerular filtration rate (GFR) and albuminuria. However, whether the association is causal remains unestablished. RESEARCH DESIGN AND METHODS: We performed a Mendelian Randomization (MR) analysis in 11,502 participants aged 40 and above, from a well-defined community in Shanghai during 2011-2013, to explore the causal association between T2D and decreased estimated GFR (eGFR) and increased urinary albumin-to-creatinine ratio (uACR). We genotyped 34 established T2D common variants in East Asians, and created a T2D-genetic risk score (GRS). We defined decreased eGFR as eGFR<90ml/min/1.73m(2) and increased uACR as uACR≥30mg/g. We used the T2D_GRS as the instrumental variable (IV) to quantify the causal effect of T2D on decreased eGFR and increased uACR. RESULTS: Each 1-standard deviation (SD, 3.90 points) increment in T2D_GRS was associated with decreased eGFR: odds ratio (OR)=1.18 (95% confidence interval [CI]: 1.01, 1.30). In the MR analysis, we demonstrated a causal relationship between genetically determined T2D and decreased eGFR (OR=1.47, 95% CI: 1.15, 1.88, P=0.0003). When grouping the genetic loci according to their relations with either insulin secretion (IS) or insulin resistance (IR), we found both IS_GRS and IR_GRS were significantly related to decreased eGFR (both P<0.02). In addition, T2D_GRS and IS_GRS were significantly associated with Log-uACR (both P=0.04). CONCLUSION: Our results provide novel evidence for a causal association between T2D and decreased eGFR by using MR approach in a Chinese population.

Diabetes and Risk of Arterial Stiffness: A Mendelian Randomization Analysis.

We aimed to explore the causal association between type 2 diabetes (T2D) and increased arterial stiffness. We performed a Mendelian randomization (MR) analysis in 11,385 participants from a well-defined community study in Shanghai during 2011-2013. We genotyped 34 T2D-associated common variants identified in East Asians and created a genetic risk score (GRS). We assessed arterial stiffness noninvasively with the measurement of brachial-ankle pulse wave velocity (baPWV). We used the instrumental variable (IV) estimator to qualify the causal relationship between T2D and increased arterial stiffness. We found each 1-SD increase in T2D_GRS was associated with 6% higher risk in increased arterial stiffness (95% CI 1.01, 1.12), after adjustment of other metabolic confounders. Using T2D_GRS as the IV, we demonstrated a causal relationship between T2D and arterial stiffening (odds ratio 1.24, 95% CI 1.06, 1.47; P = 0.008). When categorizing the genetic loci according to their effect on insulin secretion or resistance, we found genetically determined decrease in insulin secretion was associated with increase in baPWV (ßIV = 122.3 cm/s, 95% CI 41.9, 204.6; P = 0.0005). In conclusion, our results provide evidence supporting a causal association between T2D and increased arterial stiffness in a Chinese population.