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An in Vivo Atlas of Host–Pathogen Transcriptomes During Streptococcus Pneumoniae Colonization and Disease

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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 Adonis D’Melloa, Ashleigh N. Rieglerb, Eriel Martínezb, Sarah M. Benob, Tiffany D. Rickettsb, Ellen F. Foxmanc, Carlos J. Orihuelab,1, and Hervé Tettelina,1,2 aDepartment of Microbiology and Immunology, Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD 21201; bDepartment of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294; and cDepartment of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06520 Edited by Ralph R. Isberg, Tufts University School of Medicine, Boston, MA, and approved November 6, 2020 (received for review May 24, 2020) Streptococcus pneumoniae (Spn) colonizes the nasopharynx and consideration for anatomical site-specific differences. One approach can cause pneumonia. From the lungs it spreads to the blood- was the use of signature tagged mutagenesis to identify mutants that stream and causes organ damage. We characterized the in vivo are unable to replicate in vivo in an anatomical site-specific manner Spn and mouse transcriptomes within the nasopharynx, lungs, (10). Accompanying studies using microarrays to examine in vivo blood, heart, and kidneys using three Spn strains. We identified isolated RNA from the bacteria indicated that Spn gene expression Spn genes highly expressed at all anatomical sites and in an organ- varies according to the host site (11). Other RNA-sequencing specific manner; highly expressed genes were shown to have vital (RNA-seq) studies have also focused on the host response within roles with knockout mutants. The in vivo bacterial transcriptome the lungs upon pneumococcal infection. These have identified key during colonization/disease was distinct from previously reported genes involved in neutrophil recruitment and response to diverse Spn in vitro transcriptomes. Distinct and host gene-expression profiles strains and mutants (12, 13). Other forms of sequencing-based were observed during colonization and disease states, revealing spe- Spn studies, such as transposon sequencing (Tn-seq) have also been cific genes/operons whereby adapts to and influences host sites performed on the pneumococcus in multiple contexts, such as in vivo. We identified and experimentally verified host-defense path- in vivo survival or transmission, in multiple hosts (14–16). These MICROBIOLOGY ways induced by Spn during invasive disease, including proinflamma- studies, some of which are discussed below in the context of our tory responses and the interferon response. These results shed light on the pathogenesis of Spn and identify therapeutic targets. results, offer an important consideration when identifying vaccine candidates, for which the ideal targets would be universally dual species RNA-seq | in vivo transcriptomics | Streptococcus expressed, essential genes. However, it is important to note that Spn pneumoniae | mouse models of colonization and invasive disease | prior studies on the in vivo transcriptome of have employed Spn host–pathogen interactions only a single strain of and used comparisons to in vitro con- ditions for purposes of normalization, whereas the contrast be- tween in vitro and in vivo transcriptomes reported here suggests a he gram-positive microbe Streptococcus pneumoniae (Spn) Tasymptomatically colonizes the nasopharynx (1). It is also an more physiological method of normalization. Finally, we build and opportunistic pathogen that commonly infects young children, expand upon prior studies to provide information on the coordi- immunodeficient patients, and the elderly (2). It was estimated nation and regulation of host pathways responsible for restricting that in 2015, 192,000 to 366,000 deaths in children under 5 y of age were the result of pneumococcal infections (3). With the Significance advancement of antibiotics and introduction of the first pneu- mococcal conjugate vaccine in 2000, and subsequent vaccines, We detail host–pathogen interaction gene-expression profiles of deaths attributable to Spn have declined (3, 4). However, in- Streptococcus pneumoniae (Spn) and its infected host at disease creasing antibiotic resistance and serotype replacement have relevant anatomical sites using mice as experimental models. We been observed (5). A study conducted from 2006 to 2016 showed identify the shared and organ-specific transcriptomes of Spn, increased resistance to penicillin, amoxicillin, ceftriaxone, and show that bacterial and host gene-expression profiles are highly meropenem. Implementation of the PCV13 vaccine in 2010 (6) distinct during asymptomatic colonization versus disease-causing resulted in increased incidence of nonvaccine Spn serotypes (7). infection, and demonstrate that Spn and host genes with high Thus, despite major advances in public health, pneumococcal levels of expression contribute to pathogenesis or host defense, infections continue to be a significant cause of morbidity and respectively, making them optimal targets for intervention. mortality, and further investigations are warranted. The pneumococcus infects a variety of anatomical sites and Author contributions: C.J.O. and H.T. designed research; A.D., A.N.R., E.M., S.M.B., T.D.R., causes a range of illnesses, some resulting in acute mortality. Spn is C.J.O., and H.T. performed research; A.D., A.N.R., E.M., S.M.B., T.D.R., E.F.F., C.J.O., and H.T. analyzed data; and A.D., A.N.R., E.M., S.M.B., T.D.R., E.F.F., C.J.O., and H.T. wrote a common cause of sinusitis, otitis media, bronchitis, pneumonia, the paper. bacteremia, sepsis, and meningitis (2). Our group has previously Competing interest statement: H.T. and C.J.O. received funding from Merck, Sharpe, and shown that during bacteremic episodes, pneumococci in the Dohme under the Merck Investigator Studies Program; however, no intellectual property bloodstream can translocate into the heart and kill cardiomyocytes, is tied to this research. resulting in acute heart dysfunction (8). Invasive pneumococcal This article is a PNAS Direct Submission. disease can also lead to renal complications in pediatric patients and This open access article is distributed under Creative Commons Attribution-NonCommercial- hospitalized adults (9). NoDerivatives License 4.0 (CC BY-NC-ND). Current efforts to reduce the impact of pneumococcus on human 1C.J.O. and H.T. contributed equally to this work. health include improving the efficacy of vaccines and identifying 2To whom correspondence may be addressed. Email: [email protected]. host-directed therapies to decrease morbidity and mortality. Over This article contains supporting information online at https://www.pnas.org/lookup/suppl/ the past 20 y, several studies have examined pneumococcal gene doi:10.1073/pnas.2010428117/-/DCSupplemental. expression and virulence determinant requirements in vivo, with www.pnas.org/cgi/doi/10.1073/pnas.2010428117 PNAS Latest Articles | 1of12 Downloaded by guest on September 25, 2021 pneumococcal infection at different anatomical sites, a process and mouse genomes (Fig. 1 A and B). Samples whose curves that remains a largely open question. plateaued or approached plateauing were deemed adequate. Here we explored the transcriptome of the pneumococcus and The minimum required number of mapped Spn reads per sample its host using dual species RNA-seq at diverse host anatomical was estimated at ∼150,000 reads. Saturation was achieved for all sites in vivo. Blood, kidneys, lungs, and nasopharynx were har- samples except D39-infected kidneys and D39-colonized naso- vested from mice colonized or infected with three different Spn pharynxes that were excluded from all bacterial analyses. strains, with uninfected host tissue used as control. These data We estimated the ratios (Fig. 1 C, Bottom) of the number of provide a comprehensive view of dynamic processes impacting Spn reads (Fig. 1 C, Top) compared to total sequenced mouse bacterial and host biology as the bacterium invades distinct reads (Dataset S1) at each site. Although these ratios should not anatomical sites. be directly compared across multiple anatomical sites, and they depend not only on the bacterial burden but also on the tran- Results scriptional activity of Spn (and mouse cells) at each site, ratios Pneumococcal Burden Varies in a Strain- and Site-Specific Manner suggest that Spn infection in the lungs is highest with D39, fol- within the Mouse. To avoid strain bias, we used three Spn strains lowed by 6A-10 and TIGR4. On the other hand, TIGR4 appears each belonging to a distinct capsular serotype and multilocus se- to dominate over the other strains in the nasopharynx, followed quence type: TIGR4 (serotype 4, ST205), D39 (2, ST595), and 6A- by 6A-10, whereas D39 was more successful in thriving in the 10 (6A, ST460). To capture the host and bacterial transcriptomes blood compared to TIGR4 and 6A-10 during bacteremia. Bac- during infection, mice were challenged with each of these strains terial read proportions for these strains are consistent with their and tissue/organs collected from the nasopharynx, lungs, blood, and known virulence phenotypes in mice (17). No conclusions could kidneys (the latter lacking 6A-10 samples). Heart data (TIGR4 be drawn within the hearts as our previous study only included only) were included from our previously published study (8). the TIGR4 strain. Similarly, for kidneys we lacked 6A-10 sam- A typical obstacle when performing multispecies RNA-seq is ples, but TIGR4 appeared to perform better than D39
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