Hepatitis D: A Review.

Importance: Hepatitis D virus (HDV) infection occurs in association with hepatitis B virus (HBV) infection and affects approximately 12 million to 72 million people worldwide. HDV causes more rapid progression to cirrhosis and higher rates of hepatocellular carcinoma than HBV alone or hepatitis C virus. Observations: HDV requires HBV to enter hepatocytes and to assemble and secrete new virions. Acute HDV-HBV coinfection is followed by clearance of both viruses in approximately 95% of people, whereas HDV superinfection in an HBV-infected person results in chronic HDV-HBV infection in more than 90% of infected patients. Chronic hepatitis D causes more rapidly progressive liver disease than HBV alone. Approximately 30% to 70% of patients with chronic hepatitis D have cirrhosis at diagnosis and more than 50% die of liver disease within 10 years of diagnosis. However, recent studies suggested that progression is variable and that more than 50% of people may have an indolent course. Only approximately 20% to 50% of people infected by hepatitis D have been diagnosed due to lack of awareness and limited access to reliable diagnostic tests for the HDV antibody and HDV RNA. The HBV vaccine prevents HDV infection by preventing HBV infection, but no vaccines are available to protect those with established HBV infection against HDV. Interferon alfa inhibits HDV replication and reduces the incidence of liver-related events such as liver decompensation, hepatocellular carcinoma, liver transplant, or mortality from 8.5% per year to 3.3% per year. Adverse effects from interferon alfa such as fatigue, depression, and bone marrow suppression are common. HBV nucleos(t)ide analogues, such as entecavir or tenofovir, are ineffective against HDV. Phase 3 randomized clinical trials of bulevirtide, which blocks entry of HDV into hepatocytes, and lonafarnib, which interferes with HDV assembly, showed that compared with placebo or observation, these therapies attained virological and biochemical response in up to 56% of patients after 96 weeks of bulevirtide monotherapy and 19% after 48 weeks of lonafarnib, ritonavir, and pegylated interferon alfa treatment. Conclusions and Relevance: HDV infection affects approximately 12 million to 72 million people worldwide and is associated with more rapid progression to cirrhosis and liver failure and higher rates of hepatocellular carcinoma than infection with HBV alone. Bulevirtide was recently approved for HDV in Europe, whereas pegylated interferon alfa is the only treatment available in most countries.

HIV-2 inhibits HIV-1 gene expression via two independent mechanisms during cellular co-infection.

IMPORTANCE: Twenty-five years after the first report that HIV-2 infection can reduce HIV-1-associated pathogenesis in dual-infected patients, the mechanisms are still not well understood. We explored these mechanisms in cell culture and showed first that these viruses can co-infect individual cells. Under specific conditions, HIV-2 inhibits HIV-1 through two distinct mechanisms, a broad-spectrum interferon response and an HIV-1-specific inhibition conferred by the HIV-2 TAR. The former could play a prominent role in dually infected individuals, whereas the latter targets HIV-1 promoter activity through competition for HIV-1 Tat binding when the same target cell is dually infected. That mechanism suppresses HIV-1 transcription by stalling RNA polymerase II complexes at the promoter through a minimal inhibitory region within the HIV-2 TAR. This work delineates the sequence of appearance and the modus operandi of each mechanism.

Hepatitis D virus dual-infection among Chinese hepatitis B patient related to hepatitis B surface antigen, hepatitis B virus DNA and age.

BACKGROUND: The screening practices for hepatitis D virus (HDV) are diverse and non-standardized worldwide, and the exact prevalence of HDV is uncertain. AIM: To estimate HDV prevalence and investigate viral marker quantity trends in patients with hepatitis D. METHODS: We collected 5594 serum samples from patients with hepatitis B in Jilin Province, China (3293 males and 2301 females, age range of 2 to 89 years). We then conducted tests for hepatitis B surface antigen (HBsAg), hepatitis B Virus (HBV) DNA, anti-hepatitis D antigen (HDAg), and HDV RNA. RESULTS: We found that the prevalence of anti-HDAg and HDV RNA among hepatitis B patient were 3.6% (3.2-4.2%) and 1.2% (0.9-1.5%), respectively, 87.69% of hepatitis D patients were 51-70 years old. HDV infection screening positive rate of patients with HBV DNA levels below 2000 IU/mL (2.0%) was higher than those above 2000 IU/mL (0.2%). Among anti-HDAg positive patients, the HDV RNA positive rate was positively correlated with the HBsAg level and anti-HDAg level. There was a weak correlation between HBsAg and anti-HDAg levels among hepatitis D patients. CONCLUSION: Our study highlights the importance of considering multiple factors when assessing the severity of HDV infection, comprehensive evaluation of patients' clinical and laboratory parameters is necessary for proper diagnosis and treatment.

Activation of AIM2 by hepatitis B virus results in antiviral immunity that suppresses hepatitis C virus during coinfection.

IMPORTANCE: Clinical data suggest that Hepatitis C virus (HCV) levels are generally lower in Hepatitis B virus (HBV) co-infected patients, but the mechanism is unknown. Here, we show that HBV, but not HCV, activated absent in melanoma-2. This in turn results in inflammasome-mediated cleavage of pro-IL-18, leading to an innate immune activation cascade that results in increased interferon-γ, suppressing both viruses.

Epidemiological and Molecular Study on Tick-Borne Pathogens in Argun Port Area Near the Chinese-Russian Border.

Objective: We aim to investigate the species composition of ticks and the pathogen characteristics they carry in the Argun port area of the China-Russia border. Materials and Methods: Ticks were collected in surrounding grassland, mixed forest land, and other different habitats around the Argun port area at the Sino-Russian Border of Inner Mongolia in China in April 2019. The presence of 16 potential pathogens, including Yersinia Pestis, Francisella tularensis, Coxiella burnetii (Cb), Anaplasma sp. (Ap), spotted fever group rickettsiae (SFG Rk), Borrelia sp. (Bl), Leptospira, Bartonella spp., Babesia, Crimean-Congo hemorrhagic fever virus, tick-borne encephalitis virus, Bhanja virus, West Nile Virus, severe fever with thrombocytopenia syndrome bunyavirus, Hantaan virus, and bocavirus (boca) was analyzed by polymerase chain reaction. The DNA and amino acid sequences of tick-borne pathogens were compared for homology, and the phylogenetic trees were constructed by using Mega and Lasergene software. Results: A total of 210 ticks were collected and they belonged to three species: Dermacentor nuttalli, Ixodes persulcatus, and Haemaphysalis verticalis. Among them, 165 (78.57%) ticks tested positive for 5 pathogens, namely Ap, SFG Rk, Cb, Bl, and boca. Fifteen (7.14%) ticks were detected coinfection with two pathogens, and none were coinfected with three or more pathogens. Conclusion: This study shows the prevalence of at least five tick-borne pathogens in Argun, and there is a risk of coinfection by two pathogens in one tick. This study reveals the great importance of controlling tick-borne diseases in this region.

A Phase 3, Randomized Trial of Bulevirtide in Chronic Hepatitis D.

BACKGROUND: Coinfection with hepatitis D virus (HDV) accelerates the progression of liver disease associated with chronic hepatitis B. Bulevirtide inhibits the entry of HDV into hepatocytes. METHODS: In this ongoing phase 3 trial, patients with chronic hepatitis D, with or without compensated cirrhosis, were randomly assigned, in a 1:1:1 ratio, to receive bulevirtide subcutaneously at 2 mg per day (2-mg group) or 10 mg per day (10-mg group) for 144 weeks or to receive no treatment for 48 weeks followed by bulevirtide subcutaneously at 10 mg per day for 96 weeks (control group). Patients will complete 96 weeks of additional follow-up after the end of treatment. The primary end point was a combined response at week 48 of an undetectable HDV RNA level, or a level that decreased by at least 2 log10 IU per milliliter from baseline, and normalization of the alanine aminotransferase (ALT) level. The key secondary end point was an undetectable HDV RNA level at week 48, in a comparison between the 2-mg group and the 10-mg group. RESULTS: A total of 49 patients were assigned to the 2-mg group, 50 to the 10-mg group, and 51 to the control group. A primary end-point response occurred in 45% of patients in the 2-mg group, 48% in the 10-mg group, and 2% in the control group (P<0.001 for the comparison of each dose group with the control group). The HDV RNA level at week 48 was undetectable in 12% of patients in the 2-mg group and in 20% in the 10-mg group (P = 0.41). The ALT level normalized in 12% of patients in the control group, 51% in the 2-mg group (difference from control, 39 percentage points [95% confidence interval {CI}, 20 to 56]), and 56% in the 10-mg group (difference from control, 44 percentage points [95% CI, 26 to 60]). Loss of hepatitis B virus surface antigen (HBsAg) or an HBsAg level that decreased by at least 1 log10 IU per milliliter did not occur in the bulevirtide groups by week 48. Headache, pruritus, fatigue, eosinophilia, injection-site reactions, upper abdominal pain, arthralgia, and asthenia were more common in the 2-mg and 10-mg groups combined than in the control group. No treatment-related serious adverse events occurred. Dose-dependent increases in bile acid levels were noted in the 2-mg and 10-mg groups. CONCLUSIONS: After 48 weeks of bulevirtide treatment, HDV RNA and ALT levels were reduced in patients with chronic hepatitis D. (Funded by Gilead Sciences; MYR 301 ClinicalTrials.gov number, NCT03852719.).

Adeno-associated virus type 2 in US children with acute severe hepatitis.

As of August 2022, clusters of acute severe hepatitis of unknown aetiology in children have been reported from 35 countries, including the USA1,2. Previous studies have found human adenoviruses (HAdVs) in the blood from patients in Europe and the USA3-7, although it is unclear whether this virus is causative. Here we used PCR testing, viral enrichment-based sequencing and agnostic metagenomic sequencing to analyse samples from 16 HAdV-positive cases from 1 October 2021 to 22 May 2022, in parallel with 113 controls. In blood from 14 cases, adeno-associated virus type 2 (AAV2) sequences were detected in 93% (13 of 14), compared to 4 (3.5%) of 113 controls (P < 0.001) and to 0 of 30 patients with hepatitis of defined aetiology (P < 0.001). In controls, HAdV type 41 was detected in blood from 9 (39.1%) of the 23 patients with acute gastroenteritis (without hepatitis), including 8 of 9 patients with positive stool HAdV testing, but co-infection with AAV2 was observed in only 3 (13.0%) of these 23 patients versus 93% of cases (P < 0.001). Co-infections by Epstein-Barr virus, human herpesvirus 6 and/or enterovirus A71 were also detected in 12 (85.7%) of 14 cases, with higher herpesvirus detection in cases versus controls (P < 0.001). Our findings suggest that the severity of the disease is related to co-infections involving AAV2 and one or more helper viruses.

Adeno-associated virus 2 infection in children with non-A-E hepatitis.

An outbreak of acute hepatitis of unknown aetiology in children was reported in Scotland1 in April 2022 and has now been identified in 35 countries2. Several recent studies have suggested an association with human adenovirus with this outbreak, a virus not commonly associated with hepatitis. Here we report a detailed case-control investigation and find an association between adeno-associated virus 2 (AAV2) infection and host genetics in disease susceptibility. Using next-generation sequencing, PCR with reverse transcription, serology and in situ hybridization, we detected recent infection with AAV2 in plasma and liver samples in 26 out of 32 (81%) cases of hepatitis compared with 5 out of 74 (7%) of samples from unaffected individuals. Furthermore, AAV2 was detected within ballooned hepatocytes alongside a prominent T cell infiltrate in liver biopsy samples. In keeping with a CD4+ T-cell-mediated immune pathology, the human leukocyte antigen (HLA) class II HLA-DRB1*04:01 allele was identified in 25 out of 27 cases (93%) compared with a background frequency of 10 out of 64 (16%; P = 5.49 × 10-12). In summary, we report an outbreak of acute paediatric hepatitis associated with AAV2 infection (most likely acquired as a co-infection with human adenovirus that is usually required as a 'helper virus' to support AAV2 replication) and disease susceptibility related to HLA class II status.

HBV transcription and translation persist despite viral suppression in HBV-HIV co-infected patients on antiretroviral therapy.

BACKGROUND AND AIMS: Liver injury may persist in patients with HBV receiving antiviral therapy who have ongoing transcription and translation. We sought to assess ongoing HBV transcription by serum HBV RNA, translation by serum hepatitis B core related antigen (HBcrAg), and their associations with hepatic HBsAg and HBcAg staining in patients coinfected with HBV and HIV. METHODS: This is a cross-sectional study of 110 adults coinfected with HBV and HIV who underwent clinical assessment and liver biopsy. Immunohistochemistry (IHC) was performed for HBsAg and HBcAg. Viral biomarkers included quantitative HBsAg, HBV RNA, and HBcrAg. RESULTS: Participants' median age was 49 years (male, 93%; Black, 51%; HBeAg+, 65%), with suppressed HBV DNA (79%) and undetectable HIV RNA (77%) on dually active antiretroviral therapy. Overall, HBV RNA and HBcrAg were quantifiable in 81% and 83%, respectively (96% and 100% in HBeAg+, respectively). HBcAg staining was detected in 60% and HBsAg in 79%. Higher HBV RNA was associated with higher HBcAg and HBsAg IHC grades (both p < 0.0001). The HBsAg membranous staining pattern was significantly associated with higher HBV-RNA and HBcrAg levels. CONCLUSION: HBcAg and HBsAg IHC staining persisted despite viral suppression, and IHC grades and staining patterns correlated with markers of transcription (HBV RNA) and translation (HBcrAg). These data indicate that apparent HBV suppression is associated with residual transcription and translation that could contribute to liver pathology. Additional antiviral strategies directed to HBV protein expression may be useful to ameliorate liver injury.

Markers of Immune Activation and Inflammation Are Associated with Higher Levels of Genetically-Intact HIV in HIV-HBV Co-Infected Individuals.

Co-infection with hepatitis B (HBV) and human immunodeficiency virus (HIV) increases overall and liver-related mortality. In order to identify interactions between these two viruses in vivo, full-length HIV proviruses were sequenced from a cohort of HIV-HBV co-infected participants and from a cohort of HIV mono-infected participants recruited from Bangkok, Thailand, both before the initiation of antiretroviral therapy (ART) and after at least 2 years of ART. The co-infected individuals were found to have higher levels of genetically-intact HIV proviruses than did mono-infected individuals pre-therapy. In these co-infected individuals, higher levels of genetically-intact HIV proviruses or proviral genetic-diversity were also associated with higher levels of sCD14 and CXCL10, suggesting that immune activation is linked to more genetically-intact HIV proviruses. Three years of ART decreased the overall level of HIV proviruses, with fewer genetically-intact proviruses being identified in co-infected versus mono-infected individuals. However, ART increased the frequency of certain genetic defects within proviruses and the expansion of identical HIV sequences. IMPORTANCE With the increased availability and efficacy of ART, co-morbidities are now one of the leading causes of death in HIV-positive individuals. One of these co-morbidities is co-infection with HBV. However, co-infections are still relatively understudied, especially in countries where such co-infections are endemic. Furthermore, these countries have different subtypes of HIV circulating than the commonly studied HIV subtype B. We believe that our study serves this understudied niche and provides a novel approach to investigating the impact of HBV co-infection on HIV infection. We examine co-infection at the molecular level in order to investigate indirect associations between the two viruses through their interactions with the immune system. We demonstrate that increased immune inflammation and activation in HBV co-infected individuals is associated with higher HIV viremia and an increased number of genetically-intact HIV proviruses in peripheral blood cells. This leads us to hypothesize that inflammation could be a driver in the increased mortality rate of HIV-HBV co-infected individuals.

The Host Response to Influenza A Virus Interferes with SARS-CoV-2 Replication during Coinfection.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza A virus (IAV) represent two highly transmissible airborne pathogens with pandemic capabilities. Although these viruses belong to separate virus families-SARS-CoV-2 is a member of the family Coronaviridae, while IAV is a member of the family Orthomyxoviridae-both have shown zoonotic potential, with significant animal reservoirs in species in close contact with humans. The two viruses are similar in their capacity to infect human airways, and coinfections resulting in significant morbidity and mortality have been documented. Here, we investigate the interaction between SARS-CoV-2 USA-WA1/2020 and influenza H1N1 A/California/04/2009 virus during coinfection. Competition assays in vitro were performed in susceptible cells that were either interferon type I/III (IFN-I/-III) nonresponsive or IFN-I/-III responsive, in addition to an in vivo golden hamster model. We find that SARS-CoV-2 infection does not interfere with IAV biology in vivo, regardless of timing between the infections. In contrast, we observe a significant loss of SARS-CoV-2 replication following IAV infection. The latter phenotype correlates with increased levels of IFN-I/-III and immune priming that interferes with the kinetics of SARS-CoV-2 replication. Together, these data suggest that cocirculation of SARS-CoV-2 and IAV is unlikely to result in increased severity of disease. IMPORTANCE The human population now has two circulating respiratory RNA viruses with high pandemic potential, namely, SARS-CoV-2 and influenza A virus. As both viruses infect the airways and can result in significant morbidity and mortality, it is imperative that we also understand the consequences of getting coinfected. Here, we demonstrate that the host response to influenza A virus uniquely interferes with SARS-CoV-2 biology although the inverse relationship is not evident. Overall, we find that the host response to both viruses is comparable to that to SARS-CoV-2 infection alone.

Unusual SARS-CoV-2 intrahost diversity reveals lineage superinfection.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has infected almost 200 million people worldwide by July 2021 and the pandemic has been characterized by infection waves of viral lineages showing distinct fitness profiles. The simultaneous infection of a single individual by two distinct SARS-CoV-2 lineages may impact COVID-19 disease progression and provides a window of opportunity for viral recombination and the emergence of new lineages with differential phenotype. Several hundred SARS-CoV-2 lineages are currently well phylogenetically defined, but two main factors have precluded major coinfection/codetection and recombination analysis thus far: (i) the low diversity of SARS-CoV-2 lineages during the first year of the pandemic, which limited the identification of lineage defining mutations necessary to distinguish coinfecting/recombining viral lineages; and the (ii) limited availability of raw sequencing data where abundance and distribution of intrasample/intrahost variability can be accessed. Here, we assembled a large sequencing dataset from Brazilian samples covering a period of 18 May 2020 to 30 April 2021 and probed it for unexpected patterns of high intrasample/intrahost variability. This approach enabled us to detect nine cases of SARS-CoV-2 coinfection with well characterized lineage-defining mutations, representing 0.61 % of all samples investigated. In addition, we matched these SARS-CoV-2 coinfections with spatio-temporal epidemiological data confirming its plausibility with the cocirculating lineages at the timeframe investigated. Our data suggests that coinfection with distinct SARS-CoV-2 lineages is a rare phenomenon, although it is certainly a lower bound estimate considering the difficulty to detect coinfections with very similar SARS-CoV-2 lineages and the low number of samples sequenced from the total number of infections.

Assessment of NKG2C copy number variation in HIV-1 infection susceptibility, and considerations about the potential role of lacking receptors and virus infection.

Human Immunodeficiency Virus (HIV) infection dynamics is strongly influenced by the host genetic background. NKG2C is an activating receptor expressed mainly on Natural Killer (NK) cells, and a polymorphism of copy number variation in the gene coding for this molecule has been pointed as a potential factor involved in HIV infection susceptibility. We evaluated the impact of the NKG2C deletion on HIV-1 susceptibility, with or without HBV/HCV co-infection, in a total of 780 individuals, including 385 HIV-infected patients and 395 healthy blood donors. NKG2C deletion genotyping was performed by standard PCR. To our knowledge, this is the first study to access the impact of complete NKG2C deletion among HIV-infected Brazilian individuals. The frequency of NKG2C deletion (range: 19-22%) was similar in cases and controls. No association of NKG2C deletion with HIV-1 susceptibility or influence on clinical features, HBV or HCV co-infection was observed in the evaluated population. Our findings suggest that NKG2C deletion, and the consequent absence of this receptor expression, does not directly impact HIV susceptibility, HBV/HCV-co-infection in the studied population, suggesting that other signaling pathways might be triggered and perform similar functions in cell activity in the absence of this specific receptor, preventing the development of disadvantageous phenotypes. Larger cohorts and studies involving protein expression are necessary to confirm our findings.

Evaluation of Diagnostic Microbiology Capacity and Barriers in Testing for HIV and TB at Peripheral Hospital-Based Laboratories in Oyo-State, Nigeria.

The prevalence of tuberculosis (TB) and human immunodeficiency virus (HIV) coinfection in Nigeria is currently around 19.1%. This indicates that the two diseases are still a burden on the nation"s health. The aim of this study was to evaluate the diagnostic microbiology capacity and the barriers in performing assay for TB and HIV at peripheral district-level hospital-based laboratories in Oyo State, Nigeria. Diagnostic microbiology capacity was estimated using a scale of 100-point where scores ≤ 49% were categorized as low, 50-79% fair and ≥80% good. Barriers to diagnosis were summarized in proportions. The diagnostic microbiology capacity revealed that 6 (35.3%) and 11 (64.7%) of the laboratories had "fair" and "low" capacity, respectively, to detect TB in cerebrospinal fluid/sputum. In testing for HIV, 3 (17.6%) of the laboratories had "fair capacity" and 14 (82.4%) had "low capacity" to detect CD4 count and HIV antibodies in blood serum. The major diagnostic barriers in almost all (94.1%) the laboratories were lack of culture supplies and nonavailability of reagents/testing kits. There was no diagnostic microbiology service with good capacity to facilitate case detection of HIV and TB at the peripheral hospitals. Hence there is a need to improve the supply of reagents, culture stock and testing kits. This will facilitate the detection of TB and HIV cases in peripheral communities. IMPORTANCE This study provided a snapshot knowledge of testing capabilities and commodity availability at state laboratories. The findings should inform the action of stakeholders to improve diagnostic microbiology capacity, consequently enhancing diagnostic measures in detecting human immunodeficiency virus and Mycobacterium tuberculosis.

Synergistic Pathogenicity by Coinfection and Sequential Infection with NADC30-like PRRSV and PCV2 in Post-Weaned Pigs.

Porcine reproductive and respiratory syndrome virus (PRRSV) and porcine circovirus (PCVs) are two major viruses that affect pigs. Coinfections between PRRSV and PCV2 are frequently reported in most outbreaks, with clinical presentations involving dyspnea, fever, reduced feed intake, weight loss, and death in fattening pigs. The NADC30-like PRRSV and PCV2d are the main circulating virus strains found in China. This study determines the impact of NADC30-like PRRSV and PCV2d mono-infection and coinfection on the immune system, organ pathology, and viral shedding in five-week-old post-weaned pigs. Pigs were randomly divided into six groups: PBS, PRRSV, PCV2, PRRSV-PCV2 coinfection (co), and PRRSV-PCV2 or PCV2-PRRSV sequential infections. Fever, dyspnea, decreased feed intake, weight loss, and pig deaths occurred in groups infected with PRRSV, Co-PRRSV-PCV2, and PRRSV-PCV2. The viral load was higher in Co-PRRSV-PCV2, PRRSV-PCV2, and PCV2-PRRSV than those mono-infected with PRRSV or PCV2. Additionally, cytokines (IFN-γ, TNF-α, IL-4, and IL-10) produced by pigs under Co-PRRSV-PCV2 and PRRSV-PCV2 groups were more intense than the other groups. Necropsy findings showed hemorrhage, emphysema, and pulmonary adhesions in the lungs of pigs infected with PRRSV. Smaller alveoli and widened lung interstitium were found in the Co-PRRSV-PCV2 and PRRSV-PCV2 groups. In conclusion, PRRSV and PCV2 coinfection and sequential infection significantly increased viral pathogenicity and cytokine responses, resulting in severe clinical signs, lung pathology, and death.

Time-Dependent Proinflammatory Responses Shape Virus Interference during Coinfections of Influenza A Virus and Influenza D Virus.

Both influenza A virus (IAV) and influenza D virus (IDV) are enzootic in pigs. IAV causes approximately 100% morbidity with low mortality, whereas IDV leads to only mild respiratory diseases in pigs. In this study, we performed a series of coinfection experiments in vitro and in vivo to understand how IAV and IDV interact and cause pathogenesis during coinfection. The results showed that IAV inhibited IDV replication when infecting swine tracheal epithelial cells (STECs) with IAV 24 or 48 h prior to IDV inoculation and that IDV suppressed IAV replication when IDV preceded IAV inoculation by 48 h. Virus interference was not identified during simultaneous IAV/IDV infections or with 6 h between the two viral infections, regardless of their order. The interference pattern at 24 and 48 h correlated with proinflammatory responses induced by the first infection, which, for IDV, was slower than for IAV by about 24 h. The viruses did not interfere with each other if both infected the cells before proinflammatory responses were induced. Coinfection in pigs further demonstrated that IAV interfered with both viral shedding and virus replication of IDV, especially in the upper respiratory tract. Clinically, coinfection of IDV and IAV did not show significant enhancement of disease pathogenesis, compared with the pigs infected with IAV alone. In summary, this study suggests that interference during coinfection of IAV and IDV is primarily due to the proinflammatory response; therefore, it is dependent on the time between infections and the order of infection. This study facilitates our understanding of virus epidemiology and pathogenesis associated with IAV and IDV coinfection.

Molecular Epidemic Characteristics and Genetic Evolution of Porcine Circovirus Type 2 (PCV2) in Swine Herds of Shanghai, China.

Porcine Circovirus 2 (PCV2) is a crucial swine pathogen and considered a primary causative agent of porcine circovirus-associated diseases (PCVADs), posing a serious economic threat to the swine industry across globe. The world's biggest agricultural conglomerates have teamed up to create giant commercial pig farms across Shanghai due to the proximity of this region to more affluent lean-pork markets. Since its discovery, PCV2 has displayed extraordinary genetic diversity, and its genome is swiftly evolving through a series of mutations and recombinations. However, limited information on epidemiology, molecular characteristics, vaccine cross-protection, and the co-infection rate of PCV2 with other lethal swine diseases can adversely impact the pig production in the region. To investigate the molecular epidemic characteristics and genetic evolution of PCV2, pigs with doubtful symptoms of PCVADs were sampled from various commercial pig farms with a history of PWMS and/or PDNS across Shanghai from 2014 to 2018. Our results revealed the coexistence of multiple PCV2 genotypes (PCV2b, PCV2e, and PCV2d) among Shanghai pig herds and dominance of PCV2d among them. We also found critical amino acid substitutions in epitope regions of important capsid proteins in PCV2 isolates involved in viral replication and host immune escape. Spotted mutations may favor the prevalence and survival of various PCV2 genotypes despite availability of commercial vaccines. This study also provides insight into the co-infection status of PCV2 with major lethal swine viral diseases such as PPV and PPRSV. Collectively, these investigations will contribute to understanding the molecular epidemiology and evolution of PCV2 across the region.

Prevalence and Clinical Impact of Coinfection in Patients with Coronavirus Disease 2019 in Korea.

Coinfection rates with other pathogens in coronavirus disease 2019 (COVID-19) varied during the pandemic. We assessed the latest prevalence of coinfection with viruses, bacteria, and fungi in COVID-19 patients for more than one year and its impact on mortality. A total of 436 samples were collected between August 2020 and October 2021. Multiplex real-time PCR, culture, and antimicrobial susceptibility testing were performed to detect pathogens. The coinfection rate of respiratory viruses in COVID-19 patients was 1.4%. Meanwhile, the rates of bacteria and fungi were 52.6% and 10.5% in hospitalized COVID-19 patients, respectively. Respiratory syncytial virus, rhinovirus, Acinetobacter baumannii, Escherichia coli, Pseudomonas aeruginosa, and Candida albicans were the most commonly detected pathogens. Ninety percent of isolated A. baumannii was non-susceptible to carbapenem. Based on a multivariate analysis, coinfection (odds ratio [OR] = 6.095), older age (OR = 1.089), and elevated lactate dehydrogenase (OR = 1.006) were risk factors for mortality as a critical outcome. In particular, coinfection with bacteria (OR = 11.250), resistant pathogens (OR = 11.667), and infection with multiple pathogens (OR = 10.667) were significantly related to death. Screening and monitoring of coinfection in COVID-19 patients, especially for hospitalized patients during the pandemic, are beneficial for better management and survival.

Bacterial and Viral Co-Infection in the Intestine: Competition Scenario and Their Effect on Host Immunity.

Bacteria and viruses are both important pathogens causing intestinal infections, and studies on their pathogenic mechanisms tend to focus on one pathogen alone. However, bacterial and viral co-infections occur frequently in clinical settings, and infection by one pathogen can affect the severity of infection by another pathogen, either directly or indirectly. The presence of synergistic or antagonistic effects of two pathogens in co-infection can affect disease progression to varying degrees. The triad of bacterial-viral-gut interactions involves multiple aspects of inflammatory and immune signaling, neuroimmunity, nutritional immunity, and the gut microbiome. In this review, we discussed the different scenarios triggered by different orders of bacterial and viral infections in the gut and summarized the possible mechanisms of synergy or antagonism involved in their co-infection. We also explored the regulatory mechanisms of bacterial-viral co-infection at the host intestinal immune interface from multiple perspectives.