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Pathogenic bacteria encounter various stressors while residing in the host. They respond through intricate mechanisms of gene expression regulation, ensuring their survival and adaptation. Understanding how bacteria adapt to different stress conditions through regulatory processes of specific genes requires exploring complex transcriptional responses using gene co-expression networks. We employed a large transcriptome data set comprising 32 diverse human bacterial pathogens exposed to the same 11 host-mimicking stress conditions. Using the weighted gene co-expression network analysis algorithm, we generated bacterial gene co-expression networks. By associating modular eigengene expression with specific stress conditions, we identified gene co-expression modules and stress-specific stimulons, including genes with unique expression patterns under specific stress conditions. Suggesting a new potential role of the frm operon in responding to bile stress in enteropathogenic bacteria demonstrates the effectiveness of our approach. We also revealed the regulation of streptolysin S genes, involved in the production, processing, and export of streptolysin S, a toxin responsible for the beta-hemolytic phenotype of group A Streptococcus. In a comparative analysis of stress responses in three Escherichia coli strains from the core transcriptome, we revealed shared and unique expression patterns across the strains, offering insights into convergent and divergent stress responses. To help researchers perform similar analyses, we created the user-friendly web application Co-PATHOgenex. This tool aids in deepening our understanding of bacterial adaptation to stress conditions and in deciphering complex transcriptional responses of bacterial pathogens.IMPORTANCEUnveiling gene co-expression networks in bacterial pathogens has the potential for gaining insights into their adaptive strategies within the host environment. Here, we developed Co-PATHOgenex, an interactive and user-friendly web application that enables users to construct networks from gene co-expressions using custom-defined thresholds (https://avicanlab.shinyapps.io/copathogenex/). The incorporated search functions and visualizations within the tool simplify the usage and facilitate the interpretation of the analysis output. Co-PATHOgenex also includes stress stimulons for various bacterial species, which can help identify gene products not previously associated with a particular stress condition. Unveiling gene co-expression networks in bacterial pathogens has the potential for gaining insights into their adaptive strategies within the host environment. Here, we developed Co-PATHOgenex, an interactive and user-friendly web application that enables users to construct networks from gene co-expressions using custom-defined thresholds (https://avicanlab.shinyapps.io/copathogenex/). The incorporated search functions and visualizations within the tool simplify the usage and facilitate the interpretation of the analysis output. Co-PATHOgenex also includes stress stimulons for various bacterial species, which can help identify gene products not previously associated with a particular stress condition.

Introduction: SARS-CoV-2 infection causes acute COVID-19 and may result in post-COVID syndrome (PCS). We aimed to investigate how clinicians diagnose PCS and identify associated clinical and demographic characteristics.

Methods: We analysed multiregistry data of all SARS-CoV-2 test-positive individuals in Sweden (n=1 057 174) between 1 February 2020 and 25 May 2021. We described clinical characteristics that prompt PCS diagnosis in outpatient and inpatient settings. In total, there were 6389 individuals with a hospital inpatient or outpatient diagnosis for PCS. To understand symptomatology, we examined individuals diagnosed with PCS at least 3 months after COVID-19 onset (n=6389) and assessed factors associated with PCS diagnosis.

Results: Mechanical ventilation correlated with PCS (OR 114.7, 95% CI 105.1 to 125.3) compared with no outpatient/inpatient contact during initial COVID-19. Dyspnoea (13.4%), malaise/fatigue (8%) and abnormal pulmonary diagnostic imaging findings (4.3%) were the most common features linked to PCS. We compared clinical features of PCS with matched controls (COVID-19 negative, n=23 795) and COVID-19 severity-matched patients (COVID-19 positive, n=25 556). Hypertension associated with PCS cohort (26.61%) than in COVID-19-negative (OR 17.16, 95% CI 15.23 to 19.3) and COVID-19-positive (OR 9.25, 95% CI 8.41 to 10.16) controls, although most individuals received this diagnosis before COVID-19. Dyspnoea was the second most common feature in the PCS cohort (17.2%), and new to the majority compared with COVID-19-negative (OR 54.16, 95% CI 42.86 to 68.45) and COVID-19-positive (OR 18.7, 95% CI 16.21 to 21.57) controls.

Conclusions: Our findings highlight factors Swedish physicians associate with PCS.

Objectives: To investigate the effectiveness of intravenous immunoglobulin (IVIG) as treatment for COVID-19 in immunocompromised patients.

Methods: This retrospective study investigated outcomes for immunocompromised, vaccine non-responsive, patients that between September 2022 and April 2023 received IVIG as treatment for COVID-19 in the region of Västerbotten, Sweden. We analyzed clinical data, viral load, and anti-SARS-CoV-2 IgG binding and neutralization levels of patient serum samples and IVIG production batches. Primary and secondary outcomes were clinical cure and viral clearance, respectively.

Results: Sixteen patients were analyzed. After a median COVID-19 duration of 4 weeks, a median 60 g IVIG infusion increased SARS-CoV-2 binding and neutralizing antibody levels, with broad in vitro activity against tested variants. The treatment resulted in abrogation of viremia in all patients and general improvement in 15 survivors that all met the primary endpoint. Thirteen patients met the secondary endpoint at follow-up after a median of four months. Two subjects with persistent SARS-CoV-2 carriage relapsed but were successfully retreated with IVIG.

Conclusions: Antibodies in IVIG efficiently neutralized several SARS-CoV-2 variants. Treatment with IVIG was associated with clinical cure and viral clearance in immunocompromised patients. Our data suggests that IVIG could be a novel treatment alternative for COVID-19 for this patient category.

mRNA vaccines are likely to become widely used for the prevention of infectious diseases in the future. Nevertheless, a notable gap exists in mechanistic data, particularly concerning the potential effects of sequential mRNA immunization or preexisting immunity on the early innate immune response triggered by vaccination. In this study, healthy adults, with or without documented prior SARS-CoV-2 infection, were vaccinated with the BNT162b2/Comirnaty mRNA vaccine. Prior infection conferred significantly stronger induction of proinflammatory and type I IFN-related gene signatures, serum cytokines, and monocyte expansion after the prime vaccination. The response to the second vaccination further increased the magnitude of the early innate response in both study groups. The third vaccination did not further increase vaccine-induced inflammation. In vitro stimulation of PBMCs with TLR ligands showed no difference in cytokine responses between groups, or before or after prime vaccination, indicating absence of a trained immunity effect. We observed that levels of preexisting antigen-specific CD4 T cells, antibody, and memory B cells correlated with elements of the early innate response to the first vaccination. Our data thereby indicate that preexisting memory formed by infection may augment the innate immune activation induced by mRNA vaccines.

Background: Olfactory dysfunction together with neurological and cognitive symptoms are common after COVID-19. We aimed to study whether performance on olfactory and neuropsychological tests following infection predict post-COVID condition (PCC), persisting symptoms, and reduced health-related quality of life.

Methods: Both hospitalized (N = 10) and non-hospitalized individuals (N = 56) were enrolled in this prospective cohort study. Participants were evaluated 1–3 months after infection with an olfactory threshold test and neuropsychological tests, which was used as predictors of PCC. A questionnaire outlining persisting symptoms and the validated instrument EuroQol five-dimension five-level for health-related quality of life assessment were used as outcome data 1 year after infection (N = 59). Principal component analysis was used to identify relevant predictors for PCC at 1 year.

Results: Objectively assessed olfactory dysfunction at 1–3 months post infection, but not subjective olfactory symptoms, predicted post-COVID condition with reduced health-related quality of life (PCC+) at 1 year. The PCC+ group scored more often below the cut off for mild cognitive impairment on the Montreal Cognitive Assessment (61.5% vs. 21.7%) and higher on the Multidimensional Fatigue Inventory-20, compared to the group without PCC+.

Conclusion: Our results indicate that objectively assessed, olfactory dysfunction is a predictor for PCC+. These findings underscore the importance of objective olfactory testing. We propose that olfactory screening in the early post-acute phase of COVID-19 infection might identify individuals that are at higher risk of developing long-term health sequalae.

We previously demonstrated that the lungs of deceased COVID-19 patients were filled with a clear hydrogel consisting of hyaluronan (HA). In this translational study, we investigated the role of HA at all stages of COVID-19 disease to map the consequences of elevated HA on morbidity and identify the mechanism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced HA production. A reduced alveolar surface area was observed in the lungs of deceased COVID-19 patients compared to healthy controls, as visualized by a 3D rendering of lung morphology using light-sheet fluorescence microscopy. We confirmed the presence of HA in lung biopsies and found large quantities of proinflammatory fragmented HA. The association of systemic HA in blood plasma and disease severity was assessed in patients with mild (WHO Clinical Progression Scale, WHO-CPS, 1–5) and severe COVID-19 (WHO-CPS, 6–9) during the acute and convalescent phases and related to lung function. We found that systemic levels of HA were high during acute COVID-19 disease, remained elevated during convalescence, and were associated with a reduced diffusion capacity. In vitro 3D-lung models, differentiated from primary human bronchial epithelial cells, were used to study the effects of SARS-CoV-2 infection on HA metabolism, and transcriptomic analyses revealed a dysregulation of HA synthases and hyaluronidases, both contributing to increased HA in apical secretions. Furthermore, corticosteroid treatment reduced the inflammation and downregulated HA synthases. Our findings demonstrate that HA plays a role in COVID-19 morbidity and that sustained elevated HA concentrations may contribute to long-term respiratory impairment.

Lyme disease is a vector-borne illness caused by spirochetes belonging to the Borrelia burgdorferi species group. These bacteria employ several mechanisms to survive within the vertebrate host, including evasion of the complement system. In this study, we examine the protection against human serum killing by the binding of host complement regulators C4b-binding protein (C4BP) and factor H (FH) to the bacterial surface of B. burgdorferi. Via serum depletion of isolated complement regulators, we found that the absence of C4BP did not alter the survival of B. burgdorferi strain B31; however, the removal of FH increased the sensitivity of this strain to human serum as previously described. The B. garinii seabird-isolated strain Far04, on the other hand, did not bind any complement regulators of human origin and was serum-sensitive, indicating its special host species specificity.

Background: The current SARS-CoV-2 pandemic has highlighted a need for easy and safe blood sampling in combination with accurate serological methodology. Venipuncture for testing is usually performed by trained staff at healthcare centres. Long travel distances to healthcare centres in rural regions may introduce a bias of testing towards relatively large communities with closer access. Rural regions are therefore often not represented in population-based data.

Aim: The aim of this retrospective cohort study was to develop and implement a strategy for at-home testing in a rural region of Sweden during spring 2021, and to evaluate its role to provide equal health care for its inhabitants.

Methods: We developed a sensitive method to measure antibodies to the S-protein of SARS-CoV-2 and optimised this assay for clinical use together with a strategy of at-home capillary blood sampling.

Results: We demonstrated that our ELISA gave comparable results after analysis of capillary blood or serum from SARS-CoV-2-experienced individuals. We demonstrated stability of the assay under conditions that reflected temperature and humidity during winter or summer. By assessment of capillary blood samples from 4,122 individuals, we could show both feasibility of the strategy and that implementation shifted the geographical spread of testing in favour of rural areas.

Conclusion: Implementation of at-home sampling enabled citizens living in remote rural areas access to centralised and sensitive laboratory antibody tests. The strategy for testing used here could therefore enable disease control authorities to get rapid access to information concerning immunity to infectious diseases, even across vast geographical distance.

The long-term effects of COVID-19 on cognitive function have become an area of increasing concern. This paper provides an overview of characteristics, risk factors, possible mechanisms, and management strategies for cognitive dysfunction in post-COVID-19 condition (PCC). Prolonged cognitive dysfunction is one of the most common impairments in PCC, affecting between 17% and 28% of the individuals more than 12 weeks after the infection and persisting in some cases for several years. Cognitive dysfunctions can be manifested as a wide range of symptoms including memory impairment, attention deficit, executive dysfunction, and reduced processing speed. Risk factors for developing PCC, with or without cognitive impairments, include advanced age, preexisting medical conditions, and the severity of acute illness. The underlying mechanisms remain unclear, but proposed contributors include neuroinflammation, hypoxia, vascular damage, and latent virus reactivation not excluding the possibility of direct viral invasion of the central nervous system, illustrating complex viral pathology. As the individual variation of the cognitive impairments is large, a neuropsychological examination and a person-centered multidimensional approach are required. According to the World Health Organization, limited evidence on COVID-19-related cognitive impairments necessitates implementing rehabilitation interventions from established practices of similar conditions. Psychoeducation and compensatory skills training are recommended. Assistive products and environmental modifications adapted to individual needs might be helpful. In specific attention- and working memory dysfunctions, cognitive training—carefully monitored for intensity—might be effective for people who do not suffer from post-exertional malaise. Further research is crucial for evidence-based interventions specific to COVID-19-related cognitive impairments.

Background: The long-term sequelae after COVID-19 constitute a challenge to public health and increased knowledge is needed. We investigated the prevalence of self-reported persistent symptoms and reduced health-related quality of life (HRQoL) in relation to functional exercise capacity, 6 months after infection, and explored risk factors for COVID-19 sequalae.

Methods: This was a prospective, multicenter, cohort study including 434 patients. At 6 months, physical exercise capacity was assessed by a 1-minute sit-to-stand test (1MSTST) and persistent symptoms were reported and HRQoL was evaluated through the EuroQol 5-level 5-dimension (EQ-5D-5L) questionnaire. Patients with both persistent symptoms and reduced HRQoL were classified into a new definition of post-acute COVID syndrome, PACS+. Risk factors for developing persistent symptoms, reduced HRQoL and PACS+ were identified by multivariable Poisson regression.

Results: Persistent symptoms were experienced by 79% of hospitalized, and 59% of non-hospitalized patients at 6 months. Hospitalized patients had a higher prevalence of self-assessed reduced overall health (28 vs. 12%) and PACS+ (31 vs. 11%). PACS+ was associated with reduced exercise capacity but not with abnormal pulse/desaturation during 1MSTST. Hospitalization was the most important independent risk factor for developing persistent symptoms, reduced overall health and PACS+.

Conclusion: Persistent symptoms and reduced HRQoL are common among COVID-19 survivors, but abnormal pulse and peripheral saturation during exercise could not distinguish patients with PACS+. Patients with severe infection requiring hospitalization were more likely to develop PACS+, hence these patients should be prioritized for clinical follow-up after COVID-19.