Interactions between PTH and adiposity: appetizing possibilities.

Although parathyroid hormone (PTH) is best known for its role as a regulator of skeletal remodelling and calcium homeostasis, more recent evidence supports a role for it in energy metabolism and other non-classical targets. In this report, we summarize evidence for an effect of PTH on adipocytes. This review is based upon all peer-reviewed papers, published in the English language with PubMed as the primary search engine. Recent preclinical studies have documented an effect of PTH to stimulate lipolysis in both adipocytes and liver cells and to cause browning of adipocytes. PTH also reduces bone marrow adiposity and hepatic steatosis. Although clinical studies are limited, disease models of PTH excess and PTH deficiency lend support to these preclinical findings. This review supports the concept of PTH as a polyfunctional hormone that influences energy metabolism as well as bone metabolism.

Parathyroid hormone controls skeletal and circulating calcium levels. Its secretion by the four parathyroid glands is regulated primarily by the concentration of the ionized calcium level. The other major target organ for parathyroid hormone is the kidney where it conserves filtered calcium by effects on the renal tubules. While bone and the kidney are indisputably the main target organs for PTH, recent studies are pointing to systems and organs that can be shown also to respond to PTH. One of these systems that PTH appears to target is fat cells, an important storehouse for energy. This review summarizes what is known about PTH's effects to stimulate the production of energy from fat cells when present in excess or to reduce the production of energy when deficient.

Trends and Age-Period-Cohort Effect on Incidence of Male Breast Cancer from 1980 to 2019 in Taiwan and the USA.

Although male breast cancer (MBC) is globally rare, its incidence significantly increased from 1990 to 2017. The aim of this study was to examine variations in the trends of MBC incidence between populations in Taiwan and the USA from 1980 to 2019. The Taiwan Cancer Registry database and the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute of the USA were used. The age-standardized incidence rate was calculated using the world standard population in 2000. The long-term trends of the age, time period, and birth cohort effect on MBC incidence rates were estimated using the SEER Age-Period-Cohort Web Tool. The results revealed that the incidence of MBC in both countries increased from 2010 to 2019 (Taiwan: average annual percentage change (AAPC) = 2.59%; USA: AAPC = 0.64%). The age and period effects on the incidence rates in both countries strengthened, but the cohort effect was only identified in Taiwan (Rate ratio: 4.03). The identified cohort effect in this study bears resemblance to that noted in a previous investigation on female breast cancer in Taiwan. This suggests the possible presence of common environmental factors influencing breast cancer incidence in both genders, such as a high fat diet and xenoestrogen.

SARS-CoV-2 variants with NSP12 P323L/G671S mutations display enhanced virus replication in ferret upper airways and higher transmissibility.

With the emergence of multiple predominant SARS-CoV-2 variants, it becomes important to have a comprehensive assessment of their viral fitness and transmissibility. Here, we demonstrate that natural temperature differences between the upper (33°C) and lower (37°C) respiratory tract have profound effects on SARS-CoV-2 replication and transmissibility. Specifically, SARS-CoV-2 variants containing the NSP12 mutations P323L or P323L/G671S exhibit enhanced RNA-dependent RNA polymerase (RdRp) activity at 33°C compared with 37°C and high transmissibility. Molecular dynamics simulations and microscale thermophoresis demonstrate that the NSP12 P323L and P323L/G671S mutations stabilize the NSP12-NSP7-NSP8 complex through hydrophobic effects, leading to increased viral RdRp activity. Furthermore, competitive transmissibility assay reveals that reverse genetic (RG)-P323L or RG-P323L/G671S NSP12 outcompetes RG-WT (wild-type) NSP12 for replication in the upper respiratory tract, allowing markedly rapid transmissibility. This suggests that NSP12 P323L or P323L/G671S mutation of SARS-CoV-2 is associated with increased RdRp complex stability and enzymatic activity, promoting efficient transmissibility.

Modulation of gut microbiota ecosystem by a glucan-rich snail mucin heteropolysaccharide attenuates loperamide-induced constipation.

The present study aimed to investigate the effect of oral administration of snail-derived mucin extract (SM) on ameliorating constipation symptoms of loperamide-induced constipated rats (n = 6). The analytical results indicated that SM mainly contains a glucan-rich snail mucin heteropolysaccharide with high molecular weights (108.5-267.9 kDa), comprising primarily of glucose (64.9 %) and galactose (22.4 %) with some deoxyhexoses (5.0 %) and hexosamines (4.9 %). Daily SM administration at doses of 10-40 mg/kg/day to the loperamide-induced constipated rats significantly (p < 0.05) ameliorated the deterioration in fecal parameters, such as numbers and weight of feces, fecal water contents, and gastrointestinal transit ratio. The histomorphometric results showed that the loperamide-induced decreases in the thickness of mucosal and muscularis mucosae layers as well as the distribution of mucin and c-KIT-positive areas were significantly (p < 0.05) improved via SM consumption at all doses tested. SM administration at all doses significantly increased the expression of genes encoding tryptophan hydroxylases (TPH1 and TPH2; p < 0.05), tight junction molecules (OCLN, CLDN1, and TJP1; p < 0.05), and mucin (MUC2 and MUC4; p < 0.05), but significantly decreased the aquaporin-encoding genes (AQP3 and AQP8; p < 0.05). Gut microbial community analysis indicated that SM administration could modulate loperamide-induced dysbiosis by increasing the phyla Actinobacteria (11.72-12.64 % at 10-40 mg/kg doses; p < 0.05) and Firmicutes (79.33 % and 74.24 % at 20 and 40 mg/kg doses; p < 0.05) and decreasing the phyla Bacteroidetes (5.98-12.47 % at 10-40 mg/kg doses; p < 0.05) and Verrucomicrobia (2.21 % and 2.78 % at 20 and 40 mg/kg doses; p < 0.05), suggesting that SM administration is effective in ameliorating constipation by controlling gut microbial communities. These findings can be utilized as fundamental data for developing novel functional materials using SM to prevent or treat constipation.

Trends and sex-specific incidence of upper urinary tract cancer in Taiwan: A birth cohort study.

BACKGROUND: Taiwan has one of the highest incidences of upper tract urothelial cancer (UTUC) worldwide, especially in women; however, no nationwide, long-term follow-up study has evaluated this. METHODS: We investigated the incidence of UTUC in Taiwan using data from the national population-based Taiwan Cancer Registry database (1985-2019). We divided the birth cohort into nine 5-year age groups and calculated the age-specific incidence for these groups according to the corresponding birth years. RESULTS: The average annual percent change in the incidence of renal pelvis cancer from 1985 to 2019 showed sex-specific differences, with 3.5% and 5.3% increases in the incidences in men and women, respectively. The age-specific incidence rate for renal pelvis cancer among women showed a gradual increase in the group with older women as well as an increase over time in each age group. The results of a birth cohort analysis revealed that younger cohorts had higher incidence rates of renal pelvis cancer than older cohorts did. CONCLUSION: We demonstrated that the incidence of UTUC is unusually high among older Taiwanese women and that younger cohorts have a high risk of UTUC than older cohorts.

Incidence trends of oral cavity, oropharyngeal, hypopharyngeal and laryngeal cancers among males in Taiwan, 1980-2019: a population-based cancer registry study.

In a country with a high prevalence of cigarette smoking, betel chewing, and alcohol drinking, cancers of the oral cavity, nasopharynx, and larynx were the fourth, twelfth and seventeenth leading causes of cancer death, respectively, for men in 2020. We analyzed patients with head and neck cancer from 1980 to 2019 from the Taiwan Cancer Registration Database and discussed the annual average percent change, average percent change, age period, and birth cohort. Obvious period effects and birth effects are seen in oral, oropharyngeal, and hypopharyngeal cancer; however, the most significant period effect was seen between 1990 and 2009, which mainly reflects the consumption of betel nuts per capita. In addition, the period effect lessens after 2010 in oral cancer and hypopharyngeal cancers, while oropharyngeal cancers remain an obvious period effect, which results from the rising prevalence of HPV. Due to the high prevalence rate of betel quid chewing and cigarette smoking in the 1990s, the government executed several acts. As a result, the age-adjusted incidence rates of oral, oropharyngeal, and hypopharyngeal cancers have flattened since 2010, which can be explained by the declining cigarette smoking rate. The strict policy indeed shows an obvious effect on the head and neck cancer incidence rates, and we expect to see a further decline in the future.

Identification of galacturonic acid-rich polysaccharide with intestinal immune system modulating activity via Peyer's patch from postbiotics of Phellinus linteus mycelial submerged culture.

Interests in the development and exploration of industrial applications of medicinal mushrooms as postbiotics have lately increased. We recently reported the potential use of Phellinus linteus mycelial-containing whole culture extract (PLME) prepared by submerged cultivation as a postbiotic that promotes immune system activation. Here, we aimed to isolate and structurally elucidate the active ingredients in PLME by activity-guided fractionation. The intestinal immunostimulatory activity was evaluated by bone marrow (BM) cell proliferation activity and related cytokine production in C3H-HeN mouse-derived Peyer's patch (PP) cells treated with polysaccharide fractions. The initially crude polysaccharide (PLME-CP) of PLME prepared using ethanol precipitation was further fractionated into four fractions (PLME-CP-0 to -III) by anion-exchange column chromatography. BM cell proliferation and cytokine production of PLME-CP-III were significantly improved compared to those of PLME-CP. PLME-CP-III was then fractionated into PLME-CP-III-1 and PLME-CP-III-2 by gel filtration chromatography. Based on the molecular weight distribution, monosaccharide, and glycosyl linkage analyses, PLME-CP-III-1 was revealed as a novel galacturonic acid-rich acidic polysaccharide and further shown to play an important role in facilitating PP-mediated intestinal immunostimulatory activity. This is the first study demonstrating the structural characteristics of a novel intestinal immune system modulating acidic polysaccharide from P. linteus mycelium-containing whole culture broth postbiotics.

Secular Trends in Incidence of Esophageal Cancer in Taiwan from 1985 to 2019: An Age-Period-Cohort Analysis.

In Taiwan, the age-standardized incidence of EC, especially esophageal squamous cell carcinoma (ESCC), has increased substantially during the past thirty years. We described the incidence trends of EC from 1985−2019 by an average annual percentage change (AAPC) and age-period-cohort model by using Taiwan Cancer Registry data. Age-period-cohort modeling was used to estimate the period and cohort effects of ESCC and esophageal adenocarcinoma (EAC). The Spearman's correlation coefficient was used to analyze the correlation between age-adjusted incidence rates of EC and the prevalence of risk factors from national surveys. The results showed the incidence rate of ESCC in men (AAPC = 4.2, 95% CI = 3.1−5.4, p < 0.001) increased prominently from 1985−1989 to 2015−2019 while that of EAC in men (AAPC = 1.2, 95% CI = 0.9−1.5, p < 0.001) and ESCC in women (AAPC = 1.7, 95% CI = 1.4−2.1, p < 0.001) increased to a lesser degree. Increased period effects were observed in ESCC in men, ESCC in women, and EAC in men. High correlations were found between the risk factors and the increased birth-cohort effects of ESCC (p < 0.05). To conclude, the incidence of ESCC in both sex and EAC in men increased with statistical significance in recent decades. The increased prevalence of risk factors from approximately 1970−1995 could explain the increased cohort effects of ESCC.

Antioxidant and Anti-Inflammatory Activities of Sargassum macrocarpum Extracts.

Oxidative stress and the inflammatory response are known to be the most important pathological factors for aging skin cells. Therefore, substances that protect skin cells from oxidative stress and inflammatory reactions of the skin have potential as functional ingredients for skin care. In the present study, we investigated the potential of Sargassum macrocarpum as an anti-inflammatory candidate for inflammatory skin disease. Antioxidant and anti-inflammatory activities are desirable properties in such functional materials. The total polyphenol content as well as antioxidant and anti-inflammatory activities were evaluated in hot-water (HES) and ethanol (EES) extracts of S. macrocarpum. The polyphenol content was higher in the HES (HES: 115.9 ± 15.3 mg GA/g, EES: 3.9 ± 0.5 mg GA/g), and the HES also had ABTS (HES: IC50 1.0 ± 0.0 mg/mL, EES: IC50 16.09 ± 0.7 mg/mL) and DPPH (HES: IC50 6.50 ± 0.3 mg/mL, EES: IC50 35.3 ± 3.1 mg/mL) radical scavenging capacities as well as FRAP activity (HES: IC50 18.8 ± 0.4 mg/mL, EES: IC50 n.d.). Compared with the EES at the equivalent concentration range (1.25-20 µg/mL), the HES exerted a more potent inhibitory activity on LPS-stimulated nitric oxide (10.3-43.1%), IL-6 (15.7-45.0%), and TNF-α (14.1-20.8%) in RAW 264.7 macrophage cells in addition to TNF-α and IFN-γ-facilitated IL-6 (10.9-84.1%) and IL-8 (7.7-73.2%) in HaCaT keratinocytes. These results suggested that water-soluble materials might be deeply involved in the antioxidant and anti-inflammatory activity in S. macrocarpum. General composition analysis indicated that the HES contains more carbohydrates and polyphenols than the EES, and the monosaccharide composition analysis suggested that fucose-containing sulfated polysaccharide and ß-glucan might be potent anti-inflammatory candidates in the HES. The present study presents important preliminary results and a valuable strategy for developing novel anti-skin dermatitis candidates using a hot-water extract of S. macrocarpum.

SARS-CoV-2 variants show temperature-dependent enhanced polymerase activity in the upper respiratory tract and high transmissibility.

With the convergent global emergence of SARS-CoV-2 variants of concern (VOC), a precise comparison study of viral fitness and transmission characteristics is necessary for the prediction of dominant VOCs and the development of suitable countermeasures. While airway temperature plays important roles in the fitness and transmissibility of respiratory tract viruses, it has not been well studied with SARS-CoV-2. Here we demonstrate that natural temperature differences between the upper (33°C) and lower (37°C) respiratory tract have profound effects on SARS-CoV-2 replication and transmission. Specifically, SARS-COV-2 variants containing the P323L or P323L/G671S mutation in the NSP12 RNA-dependent RNA polymerase (RdRp) exhibited enhanced RdRp enzymatic activity at 33°C compared to 37°C and high transmissibility in ferrets. MicroScale Thermophoresis demonstrated that the NSP12 P323L or P323L/G671S mutation stabilized the NSP12-NSP7-NSP8 complex interaction. Furthermore, reverse genetics-derived SARS-CoV-2 variants containing the NSP12 P323L or P323L/G671S mutation displayed enhanced replication at 33°C, and high transmission in ferrets. This suggests that the evolutionarily forced NSP12 P323L and P323L/G671S mutations of recent SARS-CoV-2 VOC strains are associated with increases of the RdRp complex stability and enzymatic activity, promoting the high transmissibility.

Immunostimulatory Effect of Postbiotics Prepared from Phellinus linteus Mycelial Submerged Culture via Activation of Spleen and Peyer's Patch in C3H/HeN Mice.

Medicinal mushrooms are an important natural resource promoting health benefits. Herein, Phellinus linteus mycelia were prepared under submerged cultivation, the mycelium-containing culture broth was extracted as a whole to obtain the postbiotic materials (PLME), and its effect on the immune system was evaluated in normal C3H/HeN mice. Oral administration of PLME for 4 weeks was well tolerated and safe. In the PLME-administered groups, in addition to the production of immunostimulatory cytokines, such as interferon gamma (IFN-γ), tumor necrosis factor-α (TNF-α), and interleukin 6 (IL-6), the mitogenic activity was significantly increased. PLME administration also significantly increased the levels of serum immunoglobulin G (IgG) and IgA in the small intestinal fluid and Peyer's patches and enhanced Peyer's patch-mediated bone marrow cell proliferation activity and cytokine production (IL-2, IL-6, and IFN-γ). Histomorphometric analyses showed an increase in immune cells in the spleen and small intestinal tissues of mice administered PLME, supporting the rationale for its immune system activation. PLME mainly contained neutral sugar (969.1 mg/g), comprising primarily of glucose as a monosaccharide unit. The ß-glucan content was 88.5 mg/g. Data suggest that PLME effectively promote immune function by stimulating the systemic immune system through the spleen and intestinal immune tissues. PLME can thus be developed as a functional ingredient to enhance immune functions.

Secular trends of intrahepatic cholangiocarcinoma in a high endemic area: A population-based study.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is one of the most aggressive malignancies. However, because of its scarcity there are limited population-based data available for investigations into its epidemiologic characteristics. In Taiwan, we have a national cancer registry database that can be used to evaluate the secular trends of ICC. AIM: To evaluate secular trends of ICC according to age, sex, and risk factors in Taiwan. METHODS: In this population-based study, we used the national Taiwan Cancer Registry database. Age-standardized and relative percent changes in incidence rates were used to describe secular trends in incidence rates and sex ratios of ICC in Taiwan. RESULTS: The age-standardized ICC incidence rate among males increased from 1.51 per 100000 in 1993-1997 to 4.07 per 100000 in 2013-2017 and among female from 1.73 per 100000 to 2.95 per 100000. The incidence in females tended to plateau after 2008-2012. For males, the ICC incidence increased as age increased. In the long-term incidence trend of ICC in females, the incidence of the four age groups (40-44, 45-49, 50-54 and 55-59 years) remained stable in different years; although, the incidence of the 60-64 group had a peak in 2003-2007, and the peak incidence of the 65-69 and 70-74 groups occurred in 2008-2012. Among males, beginning at the age of 65, there were increases in the incidence of ICC for the period of 2003-2017 as compared with females in the period of 2003-2017. CONCLUSION: Increased incidence of ICC occurred in Taiwan over the past two decades. The increased incidence has progressively shifted toward younger people for both males and females.

Management of Hypoparathyroidism.

Hypoparathyroidism (HypoPT) is a rare disorder characterized by hypocalcemia in the presence of a low or inappropriately normal parathyroid hormone level. HypoPT is most commonly seen after neck surgery, which accounts for approximately 75% of cases, whereas approximately 25% have HypoPT due to nonsurgical causes. In both groups of patients, conventional therapy includes calcium and active vitamin D analogue therapy aiming to maintain serum calcium concentration in the low normal or just below the normal reference range and normalize serum phosphorus, magnesium concentrations, and urine calcium levels. The limitations of conventional therapy include wide fluctuations in serum calcium, high pill burden, poor quality of life, and renal complications. Parathyroid hormone (PTH) replacement therapy may improve the biochemical profile in those in whom conventional therapy proves unsatisfactory. Based on a systematic review and meta-analysis of the literature, the panel made a graded recommendation suggesting conventional therapy as first line therapy rather than administration of PTH (weak recommendation, low quality evidence). When conventional therapy is deemed unsatisfactory, the panel considers use of PTH. Because pregnancy and lactation are associated with changes in calcium homeostasis, close monitoring is required during these periods with appropriate adjustment of calcium and active vitamin D analogue therapy to ensure that serum calcium remains in the mid to low normal reference range in order to avoid maternal and fetal complications. Emerging therapies include molecules with prolonged PTH action as well as different mechanisms of action that may significantly enhance drug efficacy and safety. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Initial Assessment and Monitoring of Patients with Chronic Hypoparathyroidism: A Systematic Current Practice Survey.

Chronic hypoparathyroidism (HypoPT) is associated with significant morbidity and impaired quality of life (QoL). The goals of management for chronic HypoPT include improvement in QoL and the prevention of both hypo- and hypercalcemia symptoms and long-term complications. Several groups have provided consensus statements and guidelines on the management of HypoPT; however, due to limited evidence, these recommendations have largely been based on literature reviews, expert opinion, and consensus statements. The objective of this study was to use a systematic approach to describe current practice for the initial assessment and follow-up of patients with chronic HypoPT. We developed a survey asking experts in the field to select the responses that best reflect their current practice. The survey found no differences in responses between nonsurgical and postsurgical patient assessment. For new patients, respondents usually performed an assessment of serum lab profile (calcium [either albumin-adjusted or ionized], magnesium, creatinine, phosphate, 25-hydroxyvitamin D), 24-hour urine (creatinine, calcium), and a renal ultrasound to evaluate for the presence of nephrocalcinosis or nephrolithiasis. For follow-up patients, most respondents perform blood tests and urine tests every 6 months or less frequently. The reported clinical practice patterns for monitoring for complications of chronic HypoPT vary considerably among respondents. Based on the responses in this systematic expert practice survey, we provide practice suggestions for initial assessment and follow-up of patients with chronic HypoPT. In addition, we highlight areas with significant variation in practice and identify important areas for future research. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Infection Route Impacts the Pathogenesis of Severe Fever with Thrombocytopenia Syndrome Virus in Ferrets.

The threat of severe fever with thrombocytopenia syndrome (SFTS) to public health has been increasing due to the rapid spread of the ticks that carry the causative viral agent. The SFTS virus (SFTSV) was first identified in China and subsequently detected in neighboring countries, including South Korea, Japan, and Vietnam. In addition to the tick-mediated infection, human-to-human transmission has been recently reported with a high mortality rate; however, differential study of the pathogen has been limited by the route of infection. In this study, we investigated the pathogenic potential of SFTSV based on the infection route in aged ferrets, which show clinical signs similar to that of human infections. Ferrets inoculated with SFTSV via the intramuscular and subcutaneous routes show clinical signs comparable to those of severe human infections, with a mortality rate of 100%. Contrastingly, intravascularly infected ferrets exhibit a comparatively lower mortality rate of 25%, although their early clinical signs are similar to those observed following infection via the other routes. These results indicate that the infection route could influence the onset of SFTS symptoms and the pathogenicity of SFTSV. Thus, infection route should be considered in future studies on the pathogenesis of SFTSV infection.

Selection of minimally invasive surgical approaches for treating esophageal cancer.

Minimally invasive esophagectomy has gradually been accepted as an active treatment option for surgery of esophageal cancer. However, there is no consensus about how to perform the procedures in the thoracic and abdominal phase including anastomosis in the neck (McKeown) or chest (Ivor Lewis), VATS, robotic-assisted or reduced port approaches or various endoscopic abrasion techniques. Further studies to investigate the roles of these novel techniques are required to treat the various patient populations.

Ameliorating the efficacy of galacto-oligosaccharides on ovalumin-induced allergic dermatitis symptoms in Balb/c mice by regulating Th2 immune response and the ecosystem of gut microbiota.

In this study, we evaluated the effect of oral administration of galacto-oligosaccharide (GOS), famous biological molecules that are comprised of galactose and lactose, on ovalbumin (OVA)-induced allergic dermatitis. OVA-induced mice were divided into the OVA-administered group (OVA-C), promethazine hydrochloride-administered group (PC), and 100 and 200 mg kg-1 GOS-administered groups (GL and GH, respectively). GOS administration significantly improved epidermal thickness and decreased CD4+ cell numbers. The concentrations of IgE, OVA-specific IgE, and inflammatory cytokines (IL-4, IL-5, and INF-γ) in GH group mice were significantly lower than those in OVA-C group mice. Firmicutes and Bacteroidetes were identified as the major phyla in the intestinal microbiota in mice, and the relative abundance of Deferribacteres was significantly lower in the GH group than in the OVA-C group. Deferribacteraceae and Mucispirillum species were significantly lower in the GH group than in the OVA-C group. The relative abundance of Muribaculum species was significantly lower, but those of Lachnospira and Lactococcus species were significantly higher in the GH group than in the OVA-C group. Our results suggest that the alleviation effect of GOS on allergic dermatitis induced by OVA sensitization was achieved by regulating hypersensitive immune responses by improving the intestinal microbial ecosystem.

Viral Mimicry of Interleukin-17A by SARS-CoV-2 ORF8.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection triggers cytokine-mediated inflammation, leading to a myriad of clinical presentations in COVID-19. The SARS-CoV-2 open reading frame 8 (ORF8) is a secreted and rapidly evolving glycoprotein. Patients infected with SARS-CoV-2 variants with ORF8 deleted are associated with mild disease outcomes, but the molecular mechanism behind this is unknown. Here, we report that SARS-CoV-2 ORF8 is a viral cytokine that is similar to but distinct from interleukin 17A (IL-17A) as it induces stronger and broader human IL-17 receptor (hIL-17R) signaling than IL-17A. ORF8 primarily targeted blood monocytes and induced the heterodimerization of hIL-17RA and hIL-17RC, triggering a robust inflammatory response. Transcriptome analysis revealed that besides its activation of the hIL-17R pathway, ORF8 upregulated gene expression for fibrosis signaling and coagulation dysregulation. A naturally occurring ORF8 L84S variant that was highly associated with mild COVID-19 showed reduced hIL-17RA binding and attenuated inflammatory responses. This study reveals how SARS-CoV-2 ORF8 by a viral mimicry of the IL-17 cytokine contributes to COVID-19 severe inflammation. IMPORTANCE Patients infected with SARS-CoV-2 variants lacking open reading frame 8 (ORF8) have been associated with milder infection and disease outcome, but the molecular mechanism behind how this viral accessory protein mediates disease pathogenesis is not yet known. In our study, we revealed that secreted ORF8 protein mimics host IL-17 to activate IL-17 receptors A and C (IL-17RA/C) and induces a significantly stronger inflammatory response than host IL-17A, providing molecular insights into the role of ORF8 in COVID-19 pathogenesis and serving as a potential therapeutic target.

Coinfection with SARS-CoV-2 and Influenza A Virus Increases Disease Severity and Impairs Neutralizing Antibody and CD4+ T Cell Responses.

Given the current coronavirus disease 2019 (COVID-19) pandemic, coinfection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza A virus (IAV) is a major concern for public health. However, the immunopathogenic events occurring with coinfections of SARS-CoV-2 and IAV remain unclear. Here, we report the pathogenic and immunological consequences of SARS-CoV-2 and IAV H1N1 coinfection in the K18-hACE2 transgenic mouse model. Compared with a single infection with SARS-CoV-2 or IAV, coinfections not only prolonged the primary virus infection period but also increased immune cell infiltration and inflammatory cytokine levels in bronchoalveolar lavage fluid leading to severe pneumonia and lung damage. Moreover, coinfections caused severe lymphopenia in peripheral blood, resulting in reduced total IgG, neutralizing antibody titers, and CD4+ T cell responses against each virus. This study sheds light on the immunopathogenesis of SARS-CoV-2 and IAV coinfection, which may guide the development of effective therapeutic strategies for the treatment of patients coinfected with these viruses. IMPORTANCE The cocirculation of influenza virus merging with the COVID-19 pandemic raises a potentially severe threat to public health. Recently, increasing numbers of SARS-CoV-2 and influenza virus coinfection have been reported from many countries. It is a worrisome issue that SARS-CoV-2 coinfection with other pathogens may worsen the clinical outcome and severity of COVID-19 and increase fatality. Here, we evaluated SARS-CoV-2 and IAV coinfection using the K18-hACE2 mouse model. Coinfected mice exhibited increased mortality with prolonged IAV shedding. Furthermore, coinfected mice showed a higher level of cytokines and chemokines than a single infection condition. Interestingly, our data show that coinfected mice showed significantly fewer virus-specific and neutralizing antibodies than the mice with a single infection. Overall, this study suggests that coinfection aggravates viral pathology by impaired neutralizing antibody response.

Age-dependent pathogenic characteristics of SARS-CoV-2 infection in ferrets.

While the seroprevalence of SARS-CoV-2 in healthy people does not differ significantly among age groups, those aged 65 years or older exhibit strikingly higher COVID-19 mortality compared to younger individuals. To further understand differing COVID-19 manifestations in patients of different ages, three age groups of ferrets are infected with SARS-CoV-2. Although SARS-CoV-2 is isolated from all ferrets regardless of age, aged ferrets (≥3 years old) show higher viral loads, longer nasal virus shedding, and more severe lung inflammatory cell infiltration, and clinical symptoms compared to juvenile (≤6 months) and young adult (1-2 years) groups. Furthermore, direct contact ferrets co-housed with the virus-infected aged group shed more virus than direct-contact ferrets co-housed with virus-infected juvenile or young adult ferrets. Transcriptome analysis of aged ferret lungs reveals strong enrichment of gene sets related to type I interferon, activated T cells, and M1 macrophage responses, mimicking the gene expression profile of severe COVID-19 patients. Thus, SARS-CoV-2-infected aged ferrets highly recapitulate COVID-19 patients with severe symptoms and are useful for understanding age-associated infection, transmission, and pathogenesis of SARS-CoV-2.