BACKGROUND: Toxoplasma gondii infection affects a significant portion of the global population, leading to severe toxoplasmosis and, in immunocompromised patients, even death. During T. gondii infection, disruption of gut microbiota further exacerbates the damage to intestinal and brain barriers. Therefore, identifying imbalanced probiotics during infection and restoring their equilibrium can regulate the balance of gut microbiota metabolites, thereby alleviating tissue damage.
METHODS: Vimentin gene knockout (vim-/-) mice were employed as an immunocompromised model to evaluate the influence of host immune responses on gut microbiota balance during T. gondii infection. Behavioral experiments were performed to assess changes in cognitive levels and depressive tendencies between chronically infected vim-/- and wild-type (WT) mice. Fecal samples were subjected to 16S ribosomal RNA (rRNA) sequencing, and serum metabolites were analyzed to identify potential gut probiotics and their metabolites for the treatment of T. gondii infection.
RESULTS: Compared to the immunocompetent WT sv129 mice, the immunocompromised mice exhibited lower levels of neuronal apoptosis and fewer neurobehavioral abnormalities during chronic infection. 16S rRNA sequencing revealed a significant decrease in the abundance of probiotics, including several species of Lactobacillus, in WT mice. Restoring this balance through the administration of Lactobacillus murinus and Lactobacillus gasseri significantly suppressed the T. gondii burden in the intestine, liver, and brain. Moreover, transplantation of these two Lactobacillus spp. significantly improved intestinal barrier damage and alleviated inflammation and neuronal apoptosis in the central nervous system. Metabolite detection studies revealed that the levels of various Lactobacillus-related metabolites, including indole-3-lactic acid (ILA) in serum, decreased significantly after T. gondii infection. We confirmed that L. gasseri secreted much more ILA than L. murinus. Notably, ILA can activate the aromatic hydrocarbon receptor signaling pathway in intestinal epithelial cells, promoting the activation of CD8+ T cells and the secretion of interferon-gamma.
CONCLUSIONS: Our study revealed that host immune responses against T. gondii infection severely disrupted the balance of gut microbiota, resulting in intestinal and brain damage. Lactobacillus spp. play a crucial role in immune regulation, and the metabolite ILA is a promising therapeutic compound for efficient and safe treatment of T. gondii infection.

Recurrent opportunistic infections (OIs) in patients with severely immunosuppressed AIDS remain an unresolved medical challenge despite advancements in antiretroviral therapy (ART). To address this gap, we developed an HLA-mismatched allogeneic adoptive immune therapy (AAIT) specifically targeting this patient population. The safety and efficacy of this novel therapeutic approach were preliminarily confirmed in our phase 1 trial. Subsequently, a multicenter, open-label, controlled, phase 2a trial was conducted to evaluate the efficacy of AAIT in combination with ART compared with the conventional ART-only regimen. No difference in the incidence of adverse events (AEs) was observed between the two groups at the 96-week follow-up. AAIT treatment improved CD4+ T cell recovery at weeks 72 (P = 0.048) and 96 (P = 0.024) compared to the Control Group. Additionally, stratified analysis of patients in the AAIT Group showed that donor/recipient sex mismatch was significantly associated with the likelihood of patients achieving an immunological response (OR = 8.667; 95% CI, 2.010-37.377; P = 0.004). These findings suggest that AAIT serves as a promising adjunct therapy for improving the outcomes of patients with severely immunosuppressed AIDS. Further studies are needed to elucidate the immunological mechanisms underlying AAIT and identify the subpopulations that respond optimally to this therapeutic approach. This trial is registered at www.clinicaltrials.gov (NCT04098770).Trial registration: ClinicalTrials.gov identifier: NCT04098770.Trial registration: ClinicalTrials.gov identifier: NCT02651376.

BACKGROUND PAECILOMYCES: and Penicillium are considered as rare opportunistic pathogens in immunocompromised hosts, and pneumonia caused by Paecilomyces and Penicillium is rare. In this study, we present first case of severe pneumonia with pleural effusion caused by co-infection of Paecilomyces variotii (P. variotii) and Penicillium oxalicum (P. oxalicum) in a 66-year-old female with poorly controlled type 2 diabetes. CASE PRESENTATION: A 56-year-old woman patient presented to hospital for nausea, poor appetite, and vomiting for one day. On the second day of admission, blood culture and renal puncture fluid culture grew multidrug-resistant Escherichia coli (imipenem/cilastatin sensitive), and she received combination therapy with imipenem/cilastatin (1 g, every 8 h) and vancomycin (0.5 g, every 12 h). On the fourth day, she developed symptoms of respiratory failure. Pulmonary computed tomography (CT) showed an increase in pneumonia compared to before, with minor pleural effusion on both sides. Two fungi were isolated repeatedly from BALF culture, which were confirmed as P. variotii and P. oxalicum by Internal transcribed spacer (ITS) sequencing. Her pleural effusion was completely absorbed, pneumonia symptoms have significantly improved and discharged with receiving liposomal amphotericin B treatment for four weeks. CONCLUSIONS: It is worth noting that clinicians and laboratory personnel should not simply consider Paecilomyces and Penicillium species as contaminants, especially in immunocompromised patients. Early fungal identification and antifungal drug sensitivity are crucial for clinical drug selection and patient prognosis.

Fungal orbital cellulitis is usually seen in immunocompromised individuals, and opportunistic pathogens are the main etiology. We herein report a case of fungal orbital cellulitis due to Aspergillus in a patient with no history of trauma. A 48-year-old man presented to the emergency room of our hospital with a 2-week history of periorbital swelling, conjunctival hyperemia, and chemosis of his right eye. The visual acuity of his right eye was 6/20, and the intraocular pressure was 44 mmHg. The main clinical findings were proptosis of the right ocular globe with conjunctival hyperemia and a palpable infratemporal orbital mass. Laboratory testing failed to detect the presence of a pathogenic infection, and the lesions on computed tomography images resembled those of a malignant tumor of the orbit. The diagnosis was finally confirmed by postoperative pathological examination, and the patient responded favorably to debridement combined with antifungal therapy. Histopathological examination may help to reveal the nature of this disease. Surgical removal of inflammatory lesions can serve as an important diagnostic and treatment method for fungal orbital cellulitis.

A dysfunction of human host genes and proteins in coronavirus infectious disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a key factor impacting clinical symptoms and outcomes. Yet, a detailed understanding of human host immune responses is still incomplete. Here, we applied RNA sequencing to 94 samples of COVID-19 patients with and without hematological tumors as well as COVID-19 uninfected non-tumor individuals to obtain a comprehensive transcriptome landscape of both hematological tumor patients and non-tumor individuals. In our analysis, we further accounted for the human-SARS-CoV-2 protein interactome, human protein interactome, and human protein complex subnetworks to understand the mechanisms of SARS-CoV-2 infection and host immune responses. Our data sets enabled us to identify important SARS-CoV-2 (non-)targeted differentially expressed genes and complexes post-SARS-CoV-2 infection in both hematological tumor and non-tumor individuals. We found several unique differentially expressed genes, complexes, and functions/pathways such as blood coagulation (APOE, SERPINE1, SERPINE2, and TFPI), lipoprotein particle remodeling (APOC2, APOE, and CETP), and pro-B cell differentiation (IGHM, VPREB1, and IGLL1) during COVID-19 infection in patients with hematological tumors. In particular, APOE, a gene that is associated with both blood coagulation and lipoprotein particle remodeling, is not only upregulated in hematological tumor patients post-SARS-CoV-2 infection but also significantly expressed in acute dead patients with hematological tumors, providing clues for the design of future therapeutic strategies specifically targeting COVID-19 in patients with hematological tumors. Our data provide a rich resource for understanding the specific pathogenesis of COVID-19 in immunocompromised patients, such as those with hematological malignancies, and developing effective therapeutics for COVID-19.
OBJECTIVE: A majority of previous studies focused on the characterization of coronavirus infectious disease 2019 (COVID-19) disease severity in people with normal immunity, while the characterization of COVID-19 in immunocompromised populations is still limited. Our study profiles changes in the transcriptome landscape post-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in hematological tumor patients and non-tumor individuals. Furthermore, our integrative and comparative systems biology analysis of the interactome, complexome, and transcriptome provides new insights into the tumor-specific pathogenesis of COVID-19. Our findings confirm that SARS-CoV-2 potentially tends to target more non-functional host proteins to indirectly affect host immune responses in hematological tumor patients. The identified unique genes, complexes, functions/pathways, and expression patterns post-SARS-CoV-2 infection in patients with hematological tumors increase our understanding of how SARS-CoV-2 manipulates the host molecular mechanism. Our observed differential genes/complexes and clinical indicators of normal/long infection and deceased COVID-19 patients provide clues for understanding the mechanism of COVID-19 progression in hematological tumors. Finally, our study provides an important data resource that supports the increasing value of the application of publicly accessible data sets to public health.

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OBJECTIVE: We aimed to show the increasing incidence of invasive fungal infections due to Volvariella Volvacea in patients with immunosuppression.
METHODS: We present a case of an invasive fungal infection caused by Volvariella volvacea, and summarize the clinical and pathological features based on this case and a review of the literature.
RESULTS: A total of seven patients with IFIs due to Volvariella Volvacea have been reported in the literature. The majority of cases have been obtained between 2019 and 2022. Including our case, they all had acquired immunosuppression. The lung and brain were the most commonly affected organs. All eight of these patients received antifungal therapy, but five still died one to seven months after occurrences of IFIs.
CONCLUSIONS: The incidence of invasive fungal infections due to Volvariella Volvacea is increasing in recent years. It mainly occurred in patients with immunosuppression, especially in patients with malignant hematological cancers, and increased mortality.

OBJECTIVE: Early diagnosis of infectious diseases remains a challenge. This study assessed the diagnostic value of mNGS in infections and explored the effect of various factors on the accuracy of mNGS.
METHODS: An electronic article search of PubMed, Cochrane Library, and Embase was performed. A total of 85 papers were eligible for inclusion and analysis. Stata 12.0 was used for statistical calculation to evaluate the efficacy of mNGS for the diagnosis of infectious diseases.
RESULTS: The AUC of 85 studies was 0.88 (95%CI, 0.85-0.90). The AUC of the clinical comprehensive diagnosis and conventional test groups was 0.92 (95%CI, 0.89-0.94) and 0.82 (95%CI, 0.78-0.85), respectively. The results of subgroup analysis indicated that the PLR and NLR were 12.67 (95%CI, 6.01-26.70) and 0.05 (95%CI, 0.03-0.10), respectively, in arthrosis infections. The PLR was 24.41 (95%CI, 5.70-104.58) in central system infections and the NLR of immunocompromised patients was 0.08 (95%CI, 0.01-0.62).
CONCLUSIONS: mNGS demonstrated satisfactory diagnostic performance for infections, especially for bone and joint infections and central system infections. Moreover, mNGS also has a high value in the exclusion of infection in immunocompromised patients.

UNASSIGNED: We aim to identify the clinical phenotypes of immunocompromised patients with pneumonia-related ARDS, to investigate the lung microbiota signatures and the outcomes of different phenotypes, and finally, to develop a machine learning classifier for a specified phenotype.
UNASSIGNED: This prospective study included immunocompromised patients with pneumonia-related ARDS. We identified phenotypes using hierarchical clustering to analyze clinical variables and serum cytokine levels. We then compared outcomes and lung microbiota signatures between phenotypes. Based on lung microbiota markers, we developed a random forest classifier for a specified phenotype with worse outcomes.
UNASSIGNED: This study included 92 patients, who were divided into three phenotypes, namely \"type α\" (N = 33), \"type β\" (N = 12), and \"type γ\" (N = 47). Compared to type α or type β, patients with type γ had no obvious inflammatory presentation and had significantly lower IL-6 levels and more severe oxygenation failure. Type γ was also related to higher 30-day mortality and lower ventilator free days. The microbiota signatures of type γ were characterized by lower alpha diversity and distinct compositions than those of other patients. We developed a lung microbiota-derived random forest model to differentiate patients with type γ from other phenotypes.
UNASSIGNED: Immunocompromised patients with pneumonia-related ARDS can be clustered into three clinical phenotypes, namely type α, type β, and type γ. Phenotypes were distinguished from each other with different outcomes and lung microbiota signatures. Type γ, which was characterized by insufficient inflammation response and worse outcomes, can be detected with a random forest model based on lung microbiota markers.

Severe combined immunodeficient (SCID) mice serve as a critical model for human xenotransplantation studies, yet they often suffer from low engraftment rates and susceptibility to graft-versus-host disease (GVHD). Moreover, certain SCID strains demonstrate \'immune leakage\', underscoring the need for novel model development. Here, we introduce an SCID mouse model with a targeted disruption of the dclre1c gene, encoding Artemis, which is essential for V(D)J recombination and DNA repair during T cell receptor (TCR) and B cell receptor (BCR) assembly. Artemis deficiency precipitates a profound immunodeficiency syndrome, marked by radiosensitivity and compromised T and B lymphocyte functionality. Utilizing CRISPR/Cas9-mediated gene editing, we generated dclre1c-deficient mice with an NOD genetic background. These mice exhibited a radiosensitive SCID phenotype, with pronounced DNA damage and defective thymic, splenic and lymph node development, culminating in reduced T and B lymphocyte populations. Notably, both cell lines and patient-derived tumor xenografts were successfully engrafted into these mice. Furthermore, the human immune system was effectively rebuilt following peripheral blood mononuclear cells (PBMCs) transplantation. The dclre1c-knockout NOD mice described herein represent a promising addition to the armamentarium of models for xenotransplantation, offering a valuable platform for advancing human immunobiological research.