Experimental Models of Infectious Pulmonary Complications Following Hematopoietic Cell Transplantation

Abstract

Pulmonary infections remain a major cause of morbidity and mortality in hematopoietic cell transplantation (HCT) recipients. The prevalence and type of infection changes over time and is influenced by the course of immune reconstitution post-transplant. The interaction between pathogens and host immune responses is complex in HCT settings, since the conditioning regimens create periods of neutropenia and immunosuppressive drugs are often needed to prevent graft rejection and limit graft-versus-host disease (GVHD). Experimental murine models of transplantation are valuable tools for dissecting the procedure-related alterations to innate and adaptive immunity. Here we review mouse models of post-HCT infectious pulmonary complications, primarily focused on three groups of pathogens that frequently infect HCT recipients: bacteria (often P. aeruginosa), fungus (primarily Aspergillus fumigatus), and viruses (primarily herpesviruses). These mouse models have advanced our knowledge regarding how the conditioning and HCT process negatively impacts innate immunity and have provided new potential strategies of managing the infections. Studies using mouse models have also validated clinical observations suggesting that prior or occult infections are a potential etiology of noninfectious pulmonary complications post-HCT as well.

Comparing the application of mNGS after combined pneumonia in hematologic patients receiving hematopoietic stem cell transplantation and chemotherapy: A retrospective analysis

“…In contrast, the chemotherapy group was dominated by common Gram-positive cocci. Similar findings have also shown that pseudomonas aeruginosa is more prevalent after allo-HSCT and in immunocompromised patients, but is not an independent risk factor for it ( Di Pasquale et al., 2019 ; Zhou and Moore, 2021 ). Among the fungal infections, Aspergillus infections were more common in both groups, and Mucor and Candida were less common.…”

“…In terms of empirical anti-infection treatment of patients, HHV5 (CMV) was the most common virus infection in the transplantation group, while HHV7 was the most common in the chemotherapy group. Among the bacterial infections, Pseudomonas aeruginosa and Streptococcus pneumoniae were most common in the transplantation and chemotherapy groups, respectively, which may be related to the pretreatment regimen medication and long application of immunosuppressive agents in patients in the transplantation group, and it is prone to the infection of Gram-negative bacilli ( Zhou and Moore, 2021 ). In contrast, the chemotherapy group was dominated by common Gram-positive cocci.…”

“…Respiratory tract infection has long been the most common comorbidity in hematologic disease, especially in patients in the granulocyte-deficient phase of chemotherapy and those receiving allogeneic hematopoietic stem cell transplantation (allo-HSCT) ( Garcia et al., 2013 ; Kim et al., 2013 ; Beam et al., 2018 ). Also, lower respiratory tract infection has become the leading cause of death in allo-HSCT ( Nichols et al., 2004 ; Langelier et al., 2018 ; Zhou and Moore, 2021 ). mNGS requires no preconceptions, can detect multiple pathogens at once, and has been shown in several clinical studies to rapidly and accurately assist in the diagnosis of complex pulmonary infections and severe infections.…”

Pulmonary microbiome and transcriptome signatures reveal distinct pathobiologic states associated with mortality in two cohorts of pediatric stem cell transplant patients

“…In murine models of allogeneic HCT, immune responses to pathogens can be both impaired as well as exaggerated, leading to delayed phagocytosis, excessive myeloid cell recruitment and unremitting inflammation due to a lack of functional NK-and T-cells. [79][80][81][82] Our data support this paradigm in human patients and reveal a complex and heterogeneous immune response. Cluster 1, with a replete and diverse pulmonary microbiome, showed the lowest mortality rates, low levels of granulocyte activation, and low levels of lymphocyte diversity and lymphocyte-specific activation markers.…”

Pathobiological signatures of dysbiotic lung injury in pediatric patients undergoing stem cell transplantation

“…The relationship between the pulmonary microbiome, lung epithelium and the transplanted immune system is characterized by a continuous mutually influential interaction. In murine models of allogeneic HCT, immune responses to pathogens can be both impaired and exaggerated, leading to delayed phagocytosis, excessive Article https://doi.org/10.1038/s41591-024-02999-4 myeloid cell recruitment and unremitting inflammation because of a lack of functional natural killer and T cells [56][57][58][59] . Our data support this paradigm and reveal a complex heterogeneous immune response.…”