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Influenza-activated alveolar macrophages protect against death by malaria-associated acute lung injury (MA-ALI) during coinfection

ABSTRACT: Lower respiratory tract infections can be exacerbated in children living in malaria endemic areas, but there is little data on the interaction between malaria and influenza. Here we show that malaria-influenza coinfection does not yield worse prognosis in mice. Rather, coinfection with Influenza/A/X31 protects mice from severe malaria-associated acute lung injury (MA-ALI). This effect arises from differences in CD8-mediated pathology, rather than a failure by Plasmodium parasites to establish infection, and it depends on an active influenza infection in the lung. Surprisingly, recruitment of Plasmodium-reactive CD8 T cells to the lung was unaffected by influenza coinfection. Rather, an influenza-induced expansion of Arginase 1 (Arg1)-expressing alveolar macrophages suppressed the cytotoxic capabilities of pathogenic CD8 T cells once they had been recruited to the lung, rendering them harmless. Ablating this Arg1+ alveolar macrophage population in coinfected animals reverted the protective phenotype of influenza infection and reestablished death by malaria-associated pulmonary leak. Given that respiratory complications have been reported following infection by all five human-infecting Plasmodium species and the high mortality rate of MA-ALI, this study highlights suppressive alveolar macrophages as a potential therapeutic target to dampen pulmonary vascular inflammation during Plasmodium infection.

ORGANISM(S): Mus musculus

PROVIDER: GSE323359 | GEO | 2026/08/12

REPOSITORIES: GEO

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Project description:Although respiratory distress is a common complication of severe malaria, little is known about the underlying molecular basis of lung dysfunction. Animal models have provided powerful insights into the pathogenesis of severe malaria syndromes such as cerebral malaria; however, no model of malaria-induced lung injury has been definitively established. This work used bronchoalveolar lavage (BAL), histopathology and gene expression analysis to examine the development of acute lung injury (ALI) in mice infected with Plasmodium berghei ANKA (PbA). BAL fluid of PbA-infected C57BL/6 mice revealed a significant increase in IgM and total protein prior to the development of cerebral malaria (CM), indicating disruption of the alveolar-capillary membrane barrier â the physiological hallmark of acute lung injury (ALI). In contrast to sepsis-induced ALI, BAL fluid cell counts remained constant with no infiltration of neutrophils. Histopathology showed septal inflammation without cellular transmigration into the alveolar spaces. Microarray analysis comparing malaria-induced ALI with sepsis-induced ALI identified several common gene ontology groups characterizing ALI in these models, including defense and immune response. Severity of malaria-induced ALI varied in a panel of inbred mouse strains, and development of ALI correlated with peripheral parasite burden but not CM susceptibility. CD36-/- mice, which have decreased parasite lung sequestration, were relatively protected from ALI. In summary, parasite burden and CD36-mediated sequestration in the lung are primary determinants of ALI in experimental murine malaria. Furthermore, differential susceptibility of mouse strains to malaria-induced ALI and CM indicate that distinct genetic determinants likely regulate susceptibility to these two important causes of malaria-associated morbidity and mortality. Keywords: Time course Lungs were excised immediately following euthanasia, snap-frozen in liquid nitrogen and stored at â80Â°C until use. Total RNA was extracted using Trizol reagent (Invitrogen) according to the manufacturerâs instructions, and mRNA was purified using an Oligo-dT cellulose column (NEB, Mississauga, ON) as described previously [54]. cDNA with incorporated 5-(3-aminoallyl)-2âdeoxyuridine-5â-triphosphate (AAdUTP; Sigma, Oakville ON) was reverse-transcribed from 1-2 Âµg mRNA. Purified cDNA was coupled with N-hydroxysuccinimide esters of Cy3 or Cy5 (GE Lifesciences, Baie d'Urfe QC). Cy3 and Cy5-labeled cDNA pairs and Agilent control spots were added to a final volume of 0.5ml hybridization buffer (1 M NaCl, 0.5% sodium sarcosine, 50 mM methyl ethane sulfonate (MES), pH 6.5, 33% formamide and 40Âµg salmon sperm DNA (Invitrogen)). Hybridizations were performed in Agilent hybridization (Agilent, Palo Alto CA) chambers at 42Â°C with rotation for 18-24 hours. Slides were washed in 6X SSPE, 0.005% sarcosine, followed by 0.06X SSPE, allowed to dry and scanned with a 4000A microarray scanner (Axon Instruments, Union City CA). TIFF images were quantified with GenePix (Axon Instruments). Variance stabilizing normalization [55] and loess smoothing were applied in Bioconductor [56] and the data were transformed to log2 scale. Each array was hybridized with cDNA transcribed from an RNA pool of 5 C57BL/6 mice per timepoint (Day 0 and 6) and technical replicates (dye-swap) experiments were performed for both time points.

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Influenza-activated alveolar macrophages protect against death by malaria-associated acute lung injury (MA-ALI) during coinfection

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