In vivo dual RNA-seq reveals that neutrophil recruitment underlies differential tissue tropism of Streptococcus pneumoniae

Minhas, Vikrant; Aprianto, Rieza; McAllister, Lauren J.; Wang, Hui; David, Shannon C.; McLean, Kimberley T.; Comerford, Iain; McColl, Shaun R.; Paton, James C.; Veening, Jan‐Willem; Trappetti, Claudia

doi:10.1038/s42003-020-1018-x

Cited by 23 publications

(18 citation statements)

References 37 publications

(52 reference statements)

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“…Other RNA-sequencing (RNA-seq) studies have also focused on the host response within the lungs upon pneumococcal infection. These have identified key genes involved in neutrophil recruitment and response to diverse strains and mutants ( 12 , 13 ). Other forms of sequencing-based studies, such as transposon sequencing (Tn-seq) have also been performed on the pneumococcus in multiple contexts, such as in vivo survival or transmission, in multiple hosts ( 14 – 16 ).…”

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confidence: 99%

An in vivo atlas of host–pathogen transcriptomes during Streptococcus pneumoniae colonization and disease

D’Mello

Riegler

Martínez

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Streptococcus pneumoniae (Spn) colonizes the nasopharynx and can cause pneumonia. From the lungs it spreads to the bloodstream and causes organ damage. We characterized the in vivo Spn and mouse transcriptomes within the nasopharynx, lungs, blood, heart, and kidneys using three Spn strains. We identified Spn genes highly expressed at all anatomical sites and in an organ-specific manner; highly expressed genes were shown to have vital roles with knockout mutants. The in vivo bacterial transcriptome during colonization/disease was distinct from previously reported in vitro transcriptomes. Distinct Spn and host gene-expression profiles were observed during colonization and disease states, revealing specific genes/operons whereby Spn adapts to and influences host sites in vivo. We identified and experimentally verified host-defense pathways induced by Spn during invasive disease, including proinflammatory responses and the interferon response. These results shed light on the pathogenesis of Spn and identify therapeutic targets.

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confidence: 99%

An in vivo atlas of host–pathogen transcriptomes during Streptococcus pneumoniae colonization and disease

D’Mello

Riegler

Martínez

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…Although this recruitment of LysM + appears to be too slow to account for the rapid fall in CFUs over the first 30 min in the dorsal skull preparation, after the subsequent rebound, the number of CFUs begins to fall again at less than 5h post-infection, as the LysM + population approaches its maximum. It appears therefore, that the LysM + population increases until the clearance of Sp is established 68,93 , then begins to fall. Intense immune reactions in the pachymeninx (rather than the leptomeninx) have been much studied for their occurrence in migraine 21 , and also observed in experimental autoimmune encephalitis 94,95 , trypanosomiasis 41 and infection by lymphocytic choriomeningitis virus 72 .…”

Section: Discussionmentioning

confidence: 98%

Streptococcus pneumoniaerapidly translocates from the nasopharynx through the cribriform plate to invade and inflame the dura

Audshasai

Coles

Panagiotou

et al. 2021

Preprint

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The entry routes and translocation mechanisms of bacterial pathogens into the central nervous system remain obscure. We report here that Streptococcus pneumoniae (Sp) or polystyrene microspheres, applied to the nose of a mouse, appeared in the meninges of the dorsal cortex within minutes. Recovery of viable bacteria from dissected tissue and fluorescence microscopy showed that up to at least 72h, Sp and microspheres were predominantly in the outer of the two meninges, the pachymeninx. No Sp were found in blood or cerebrospinal fluid. Evidence that this was not an artifact of the method of administration is that in mice infected by horizontal transmission, Sp were also predominantly in the meninges and absent from blood. Intravital imaging through the skull, and flow cytometry showed recruitment and activation of LysM+ cells in the dorsal pachymeninx at 5h and 10h following intranasal infection. Imaging of the cribriform plate suggested that both Sp and microspheres entered through its foramina via an inward flow of fluid connecting the nose to the pachymeninx. Our findings bring further insight into the invasion mechanisms of bacterial pathogens such as Sp into the central nervous system, but are also pertinent to the delivery of drugs to the brain, and the entry of air-borne particles into the cranium.

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“…However, we do not know if the reduced efficacy of C27 in this model reflects an inability to prevent dissemination, and/or distinct features of the ST3 clinical strain, B2. Tissue specific differences in virulence have been identified for other STs (36,37), but further work is needed to dissect the roles that humAbs and ST3 strain specific differences may play in the reduced (which was not certified by peer review) is the author/funder. All rights reserved.…”

Section: Discussionmentioning

confidence: 99%

Isolation and characterization of human monoclonal antibodies to pneumococcal capsular polysaccharide 3

Babb

Doyle²,

Pirofski

2021

Preprint

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The current pneumococcal capsular polysaccharide (PPS) conjugate vaccine (PCV13) is less effective against Streptococcus pneumoniae serotype 3 (ST3), which remains a major cause of pneumococcal disease and mortality. Therefore, dissecting structure-function relationships of human PPS3 antibodies may reveal characteristics of protective antibodies. Using flow cytometry, we isolated PPS3-binding memory B cells from pneumococcal vaccine recipients and generated seven human PPS3-specific monoclonal antibodies (humAbs). Five humAbs displayed ST3 opsonophagocytic activity, four induced ST3 agglutination in vitro, and four mediated both activities. For two humAbs, C10 and C27, that used the same variable heavy (VH) and light (VL) chain domains (VH3-9*01/VL2-14*03), C10 had fewer VL somatic mutations, higher PPS3 affinity, more ST3 opsonophagocytic and agglutinating activity, whilst both humAbs altered ST3 gene expression in vitro. After VL swaps, C10VH/C27VL exhibited reduced ST3 binding and agglutination, but C27VH/C10VL binding was unchanged. In C57Bl/6 mice, C10 and C27 reduced nasopharyngeal colonization with ST3 A66 and a clinical strain, B2, and prolonged survival following lethal A66 intraperitoneal infection, but only C10 protected against lethal intranasal infection with the clinical strain. Our findings, associate efficacy of PPS3-specific humAbs with ST3 agglutination and opsonophagocytic activity and reveal an unexpected role for the VL in functional activity in vitro and in vivo. These findings also provide insights that may inform antibody-based therapy and identification of surrogates of vaccine efficacy against ST3.IMPORTANCEDespite the global success of pneumococcal conjugate vaccination, serotype 3 (ST3) pneumococcus remains a leading cause of morbidity and mortality. In comparison to other vaccine-included serotypes, the ST3 pneumococcal capsular polysaccharide (PPS3) induces a weaker opsonophagocytic response, which is considered a correlate of vaccine efficacy. Previous studies of mouse PPS3 monoclonal antibodies identified ST3 agglutination as a correlate of reduced ST3 nasopharyngeal colonization in mice, however neither the agglutinating ability of human vaccine-elicited PPS3 antibodies nor their ability to prevent experimental murine nasopharyngeal colonization has been studied. We generated and analysed the functional and in vivo efficacy of human vaccine-elicited PPS3 monoclonal antibodies and found that ST3 agglutination associated with antibody affinity, protection in vivo, and limited somatic mutations in the light chain variable region. These findings provide new insights that may inform the development of antibody-based therapies and next generation vaccines for ST3.

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In vivo dual RNA-seq reveals that neutrophil recruitment underlies differential tissue tropism of Streptococcus pneumoniae

Cited by 23 publications

References 37 publications

An in vivo atlas of host–pathogen transcriptomes during Streptococcus pneumoniae colonization and disease

An in vivo atlas of host–pathogen transcriptomes during Streptococcus pneumoniae colonization and disease

Streptococcus pneumoniaerapidly translocates from the nasopharynx through the cribriform plate to invade and inflame the dura

Isolation and characterization of human monoclonal antibodies to pneumococcal capsular polysaccharide 3

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