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Human bocavirus (HBoV) is predominantly found in the respiratory tract infections and in the stool of patients with gastroenteritis symptoms. However, data on the prevalence of HBoV genotypes in environmental samples are limited. Here we addressed the prevalence of HBoV in sewage collected from three different wastewater treatment plants in Egypt. HBoV-1, HBoV-2, and HBoV-3 were detected, whereas none of the samples were positive for HBoV-4. The median concentration of HBoV in influent samples was 8.5 × 10 GC/l for HBoV-1, 3.0 × 10 GC/l for HBoV-2, and 2.5 × 10 GC/l for HBoV-3. The concentration was reduced but not completely removed in the effluent samples. The median concentration in the outlet samples was 2.9 × 10 GC/l for HBoV-1, 4.1 × 10 GC/l for HBoV-2, and 2.1 × 10 GC/l for HBoV-3. Moreover, no seasonality pattern of HBoVs was found. The high incidence of HBoV in sewage samples provided an evidence of its circulation in the local population. Although the role of HBoV in respiratory or gastro-intestinal infections still remains to be fully elucidated, the risk of infection via contaminated water should be taken into consideration.

Hepatitis A virus (HAV) still poses a considerable problem worldwide. In the current study, hepatitis A virus was recovered from wastewater samples collected from three wastewater treatment plants over one year. Using RT-PCR, HAV was detected in 43 out of 68 samples (63.2%) representing both inlet and outlet. Eleven positive samples were subjected to sequencing targeting the VP1-2A junction region. Phylogenetic analysis revealed that all samples belonged to subgenotype IB with few substitutions at the amino acid level. The complete sequence of one isolate (HAV/Egy/BI-11/2015) showed that the similarity at the amino acid level was not reflected at the nucleotide level. However, the deduced amino acid sequence derived from the complete nucleotide sequence showed distinct substitutions in the 2B, 2C, and 3A regions. Recombination analysis revealed a recombination event between X75215 (subgenotype IA) and AF268396 (subgenotype IB) involving a portion of the 2B nonstructural protein coding region (nucleotides 3757-3868) assuming the herein characterized sequence an actual recombinant. Despite the role of recombination in picornaviruses evolution, its involvement in HAV evolution has rarely been reported, and this may be due to the limited available complete HAV sequences. To our knowledge, this represents the first characterized complete sequence of an Egyptian isolate and the described recombination event provides an important update on the circulating HAV strains in Egypt.

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Currently, all available antiviral drugs against influenza virus (IV) that target the virus proteins directly, like Baloxavir acid (BXA), lead to viral resistance. Therefore, cellular mechanisms and factors essential for IV replication are promising antiviral targets. As IV strongly depends on the virus-induced Raf/MEK/ERK signal pathway for efficient generation of infectious progeny virions, this pathway represents an important target. We aimed to determine whether the MEK inhibitor ATR-002 (PD0184264) is able to impair replication of BXA-resistant influenza A virus (IAV) and whether a treatment combining BXA and ATR-002 improves the therapeutic efficiency in vitro. A549 cells infected with different IAV strains including BXA-resistant variants were treated with ATR-002 or BXA and the effect on virus titer reduction was determined. The synergistic effect of ATR-002 and BXA was also analyzed using different evaluation methods. The data demonstrated that ATR-002 has a significant and dose-dependent inhibitory effect on IAV replication across different strains and subtypes. IAV with the PA-I38T mutation shows resistance against BXA, but is still susceptible toward ATR-002. The combination of ATR-002 and BXA exhibited a synergistic potency reflected by low combination index values. In conclusion, we show that ATR-002 permits to counteract the limitations of BXA against BXA-resistant IAV. Moreover, the results support the use of ATR-002 (i) in a mono-therapy, as well as (ii) in a combined approach together with BXA. These findings might also apply to the treatment of infections with IAV, resistant against other direct-acting antiviral compounds.

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Coronaviruses, in particular the current pandemic strains of SARS-CoV-2, represent an ever-evolving threat to human life. Currently available antiviral drugs are not suitable for severely infected patients in later hyperinflammatory stages of the disease. New therapeutics that inhibit virus propagation and target inflammation would be ideal. We demonstrate that the host targeted MEK inhibitor zapnometinib displays such a dual effect. The drug efficiently reduced virus titers of different SARS-CoV-2 variants and other highly pathogenic human coronaviruses such as SARS-CoV-1 and MERS-CoV in vitro. In a Syrian hamster infection model, zapnometinib reduced SARS-CoV-2 viral load and alleviated lung pathology. Drug safety biomarkers, body weight change and clinical observations, indicated that zapnometinib was well tolerated and showed no toxicity. Moreover, the immune dampening effect could be confirmed in an acute lung injury mouse model and in vitro experiments in primary human blood cells that demonstrated the reduction of disease related cytokines and chemokines. Thus, in contrast to direct-acting antivirals, zapnometinib displays a dual therapeutic effect highlighting its potential in the treatment of severe COVID-19 and other acute viral infections leading to hyperinflammation.