Biology subjects

Orihuela, C. J.

Publications and source records attributed to Orihuela, C. J..

12 recordsLinked to original sources

bioRxiv2026

Rescue of ribosomal protein bL27 in Streptococcus pneumoniae TIGR4 by an alternate protease

Streptococcus pneumoniae is a major human respiratory pathogen. The bacterial 70S ribosome is a target of many clinically important antibiotics. The N-terminus of ribosomal protein bL27 extends into the peptidyl transferase center and contributes to the translation process. In Firmicutes, full length bL27 contains an 8-12 amino acid N-terminal extension that is absent from Gram-negative bacteria. This extension is cleaved by the protease Prp, which is absent from organisms lacking the extension. Prp-mediated cleavage of bL27 is essential in Staphylococcus aureus, and Prp has been proposed as a potential antibiotic target. Here, we show that in S. pneumoniae strain TIGR4, a {Delta}prp mutant remained viable, and produced ribosomes containing cleaved bL27, whereas deletion of prp was not tolerated in strain D39. These results suggested the presence of an alternate bL27-processing protease in TIGR4 that was absent from D39. Using a combination of genomics, proteomics and biochemical analyses, we identified this enzyme as the product of previously uncharacterized gene SP_1145, encoding a protease that we named Ribosome rescue protease (Rrp). SP_1145 is carried on a mobile genetic element that is present in strain TIGR4, but absent from D39. Our findings shed light on an alternative mechanism for bL27 maturation, and indicate that some strains of S. pneumoniae harbor horizontally acquired redundant pathways for this essential ribosome processing step.

microbiology↗

bioRxiv2025

Biofilm formation during pneumococcal carriage imprints naturally acquired humoral immunity

Streptococcus pneumoniae (Spn) colonization of the nasopharynx is a prerequisite for transmission and invasive disease. To investigate how repeated asymptomatic colonization shapes immunity and influences bacterial traits, we developed the Repeated Asymptomatic Murine Pneumococcal Colonization (RAMPC) model using strains belonging to serotypes: 2 (D39), 3 (WU2), and 4 (TIGR4). Sequential colonization revealed strain- and exposure-order-dependent effects on bacterial burden, with initial colonization yielding robust carriage and subsequent exposures resulting in diminished burden and rapid clearance. Humoral profiling demonstrated antigenic imprinting: the first colonizing strain largely determined IgG and IgA specificity, with minimal diversification after repeated exposures. Reactivity was strongest for biofilm-associated antigens correlating with each strains biofilm-forming capacity. Using TIGR4 mutants deficient in biofilm formation, we confirmed that in vivo aggregate formation drives humoral responses. Human sera from naturally colonized adults mirrored these findings, favoring biofilm antigens independent from capsule. Protection was demonstrated as triple-colonized mice exhibited reduced mortality and bacteremia following pneumococcal pneumonia challenge. Moreover, the initial colonizing strain influenced protection against heterologous infection, underscoring the lasting imprint of the biofilm phenotype on immunity. Finally, IgA responses in nasal-associated lymphoid tissue paralleled serum IgA patterns, validating systemic measurements as a proxy for mucosal immunity. Collectively, these results reveal that biofilm formation during colonization is a key determinant of humoral immunity and protection, providing insight into pneumococcal biology and informing strategies to design next-generation interventions. Author summaryStreptococcus pneumoniae (Spn) is a leading cause of pneumonia, meningitis, and sepsis, yet its primary lifestyle is asymptomatic colonization of the nasopharynx. Understanding how colonization shapes immunity and bacterial physiology is critical for predicting disease risk and improving future vaccines. Using a novel murine model of repeated colonization and human sera from naturally colonized adults, we show that humoral immunity is strongly biased toward antigens expressed during biofilm growth, the predominant mode of Spn in the nasopharynx, rather than planktonic forms. This response is strain-dependent and imprinted by the first colonizing strain, influencing subsequent exposures and protection against pneumonia. Importantly, biofilm formation, not capsule, drives immune recognition revealing a key link between bacterial physiology and host immunity. These findings provide fundamental insight into pneumococcal biology and the host response, suggesting that targeting biofilm-associated antigens may improve vaccine design or strategies to prevent transmission and invasive disease.

microbiology↗

bioRxiv2025

Full title Capsule and PspA Cooperatively Confer Resistance of Streptococcus pneumoniae to the Human defensin HNP-1

Streptococcus pneumoniae resists host defenses through multiple virulence factors, yet their combined influence on the action of antimicrobial peptides remains unclear. We examined the role of Pneumococcal surface protein A (PspA) and the polysaccharide capsule in modulating susceptibility to the human defensin HNP-1. PspA-deficient strains of two different genetic backgrounds displayed increased sensitivity, while recombinant PspA neutralized peptide activity and anti-PspA antibodies enhanced bacterial killing. The capsule conferred serotype-dependent protection, with type 2 being more effective than type 4, and free polysaccharides acted as decoys by sequestering HNP-1. Removal of surface PspA from capsule-deficient mutants revealed additive contributions of both factors to survival. These findings highlight the complementary roles of capsule and PspA in pneumococcal resistance to HNP-1 and suggest that targeting these mechanisms could potentiate innate immune clearance and provide novel insights that may inform future vaccine design and antimicrobial strategies. AUTHOR SUMMARYStreptococcus pneumoniae causes serious infections such as pneumonia and meningitis, in part by evading the human immune system. One key component of our immune defense is antimicrobial peptides like HNP-1, which directly kill bacteria. In this study, we investigated how two major pneumococcal virulence factors - the surface protein PspA and the sugar capsule - help the bacterium resist killing by HNP-1. We found that removing PspA made the bacteria more susceptible, while adding purified PspA or blocking it with antibodies increased the peptide activity. The protective effect of the capsule depended on the sugar composition, and purified capsule sugars could bind and neutralize HNP-1, limiting its activity against pneumococci. When we removed PspA from bacteria lacking a capsule, the bacteria became even more sensitive, showing that both factors contribute to resisting immune attack. These results reveal how S. pneumoniae uses multiple strategies to survive innate immune defenses and highlight potential targets for improved vaccines or new treatments.

microbiology↗

bioRxiv2025

Cleavage of Streptococcus pneumoniae ribosomal protein L27 by the Prp protease

Streptococcus pneumoniae is one of the most important human respiratory pathogens worldwide. The increase in antibiotic resistance in S. pneumoniae and other pathogens is a significant public health concern. The streptococcal 70S ribosome is a prime target for antibiotics. Ribosomal protein L27 reaches into the peptidyl transferase center with its extended N-terminus and may be involved in the translation process. We have shown that L27 in Firmicutes, including staphylococci and streptococci, has an additional 9-12 amino acid N-terminal extension compared to Gram-negative organisms like Escherichia coli. The extension is cleaved by a protease called Prp that is absent from organisms that lack the extension. In S. aureus, Prp and the N-terminal extension of L27 are essential. Here, we have characterized the cleavage of L27 by Prp in S. pneumoniae. Prp forms dimers that efficiently cleave L27 in vitro. An inactive form of Prp (PrpC34S) binds to L27 without cleaving, whereas L27 with a mutation (F12A) of the cleavage site does not bind Prp. Overexpression of PrpC34S in vivo is detrimental to S. pneumoniae growth. Surprisingly, a S. pneumoniae {Delta}prp strain was viable, apparently due to cleavage of L27 by another, unknown protease. Unlike in S. aureus, a mutant strain lacking the N-terminal extension of L27 was viable, but showed impaired growth. Our study sheds light on a process that could be exploited for novel antibiotics, but emphasizes important differences between streptococci and staphylococci. HIGHLIGHTSO_LIRibosomal protein L27 in S. pneumoniae is N-terminally processed by Prp protease C_LIO_LIA S. pneumoniae {Delta}prp mutant is viable, but exhibits impaired growth C_LIO_LICleavage of L27 is required for viability, but the N-terminal extension is not essential C_LIO_LIIn the absence of Prp, L27 is processed by another protease. C_LIO_LIThere are distinct differences in the role of Prp between S. aureus and S. pneumoniae. C_LI

microbiology↗

bioRxiv2025

Alterations in Nutrient Availability in the Lungs During Streptococcus pneumoniae-Induced Pneumonia

Streptococcus pneumoniae is a leading cause of pneumonia. Importantly, the extent and impact of changes in the infected airway on bacterial nutrient availability and gene expression are not known. Utilizing untargeted UPLC-ESI-MS/MS metabolomics, we comprehensively characterized the metabolic landscape in the airway across early, mid, and severe stages of pneumococcal pneumonia. This revealed that dynamic shifts in metabolites occurred during pneumonia, with an initial influx of metabolites at the early stage, followed by declines as the disease progressed. Specific host metabolic perturbations were indicative of purine dysregulation, cellular stress, and outright tissue injury. Levels of glucose, a known modulator of pneumococcal capsule production, were highest at early disease stage, and then declined as the disease progressed, overlaying general metabolite trends. Concurrent bacterial transcriptome profiling was performed using a NanoString nCounter custom panel of 66 genes selected for their importance to metabolism, virulence, and stress response; 9% of which had disease-stage significant differences in gene expression. This analysis revealed remarkably high expression of spxB, the gene encoding pyruvate oxidase, at the severe stage of pneumonia compared to the mid-stage pneumonia, consistent with a drop in glucose levels and indicative of a shift towards mixed fermentation and the increased production of hydrogen peroxide. Our study improves our understanding of how pneumococcal infection alters the lung environment, driving profound metabolic shifts that, in turn, influence bacterial phenotypes. This detailed understanding of host-pathogen metabolic interactions offers valuable insights into novel therapeutic strategies.

microbiology↗

bioRxiv2024

Streamlining Marker-less Allelic Replacement in Streptococcus pneumoniae Through a Single Transformation Step Strategy: easyJanus

The ability to genetically manipulate bacteria is a staple of modern molecular microbiology. Since the 2000s, marker-less mutants of Streptococcus pneumoniae (Spn) have been made by allelic-exchange predominantly using the kanR-rpsL cassette known as "Janus". The conventional Janus protocol involves two transformation steps using multiple PCR-assembled products containing the Janus cassette and the target genes flanking DNA. We present an innovative strategy to achieve marker-less allelic replacement through a single transformation step. Our approach involves the integration of an additional gene downstream region upstream of the Janus cassette, resulting in a modified genetic arrangement. This single modification reduced the number of required PCR fragments from five to four, lowered the number of assembly reactions from two to one, and simplified the transformation process to a single step. To validate the efficacy of our approach, we implemented this strategy to delete in Spn serotype 4 strain TIGR4 the virulence gene pspA, the entire capsular polysaccharide synthesis locus cps4, and to introduce a single nucleotide replacement into the chromosome. Notably, beyond streamlining the procedure, our method markedly reduced false positives typically encountered during negative selection with streptomycin when employing the traditional Janus protocol. Furthermore, and as consequence of reducing the amount of exogenous DNA required for construct synthesis, we show that our new method is amendable to the use of commercially available synthetic DNA for construct creation, further reducing the work needed to obtain a mutant. Our streamlined strategy, termed easyJanus, substantially expedites the genetic manipulation of Spn facilitating future research endeavors. IMPORTANCEWe introduce a groundbreaking strategy aimed at streamlining the process for marker-less allelic replacement in Streptococcus pneumoniae, a Gram-positive bacterium and leading cause of pneumonia, meningitis, and ear infections. Our approach involves a modified genetic arrangement of the Janus cassette to facilitate self-excision during the segregation step. Since this new method reduces the amount of exogenous DNA required, it is highly amendable to the use of synthetic DNA for construction of the mutagenic construct. Our streamlined strategy, called easyJanus, offers significant time and cost savings, while concurrently enhancing the efficiency of obtaining marker-less allelic replacement in S. pneumoniae.

microbiology↗

bioRxiv2023

PspA-mediated aggregation protects Streptococcus pneumoniae against desiccation on fomites

Streptococcus pneumoniae (Spn) resides in the nasopharynx where it can disseminate to cause disease. One key Spn virulence factor is pneumococcal surface protein A (PspA), which promotes survival by blocking the antimicrobial peptide lactoferricin. PspA has also been shown to mediate attachment to dying epithelial cells in the lower airway due to its binding of cell surface-bound mammalian (m)GAPDH. Importantly, the role of PspA during colonization is not well understood. Wildtype Spn was present in nasal lavage elutes collected from asymptomatically colonized mice at levels [~]10-fold higher that its isogenic PspA-deficient mutant ({Delta}pspA). Wildtype Spn also formed aggregates in mucosal secretions composed of sloughed epithelial cells and hundreds of pneumococci, whereas {Delta}pspA did not. Spn within the center of these aggregates better survived prolonged desiccation on fomites than individual pneumococci and were capable of infecting naive mice, indicating PspA-mediated aggregation conferred a survival/transmission advantage. Incubation of Spn in saline containing mGAPDH also enhanced tolerance to desiccation, but only for wildtype Spn. mGAPDH was sufficient to cause low-level aggregation of wildtype Spn but not {Delta}pspA. In strain WU2, the subdomain of PspA responsible for binding GAPDH (aa230-281) is ensconced within the lactoferrin (LF)-binding domain (aa167-288). We observed that LF inhibited GAPDH-mediated aggregation and desiccation tolerance. Using surface plasmon resonance, we determined that Spn forms multimeric complexes of PspA-GAPDH-LF on its surface and that LF dislodges GAPDH. Our findings have important implications regarding pneumococcal colonization/transmission processes and ongoing PspA-focused immunization efforts for this deadly pathogen. IMPORTANCEStreptococcus pneumoniae (Spn) is a dangerous human pathogen capable of causing pneumonia and invasive disease. The virulence factor pneumococcal surface protein A (PspA) has been studied for nearly four decades with well-established roles in pneumococcal evasion of C-reactive protein and neutralization of lactoferricin. Herein, we show that mammalian (m)GAPDH in mucosal secretions promotes aggregation of pneumococci in a PspA-dependent fashion, whereas lactoferrin counters this effect. PspA-mediated GAPDH-dependent bacterial aggregation protected Spn in nasal lavage elutes and grown in vitro from desiccation on fomites. Furthermore, surviving pneumococci within these aggregates retained their ability to colonize naive hosts after desiccation. We report that Spn binds to and forms protein complexes on its surface composed of PspA, mGAPDH, and lactoferrin. Changes in the levels of these proteins therefore most likely have critical implications on Spn colonization, survival on fomites, and transmission.

microbiology↗

bioRxiv2023

Influenza A virus modulation of Streptococcus pneumoniae infection using ex vivo transcriptomics in a human primary lung epithelial cell model reveals differential host glycoconjugate uptake and metabolism

BackgroundStreptococcus pneumoniae (Spn) is typically an asymptomatic colonizer of the nasopharynx but it also causes pneumonia and disseminated disease affecting various host anatomical sites. Transition from colonization to invasive disease is not well understood. Studies have shown that such a transition can occur as result of influenza A virus coinfection. MethodsWe investigated the pneumococcal (serotype 19F, strain EF3030) and host transcriptomes with and without influenza A virus (A/California/07 2009 pH1N1) infection at this transition. This was done using primary, differentiated Human Bronchial Epithelial Cells (nHBEC) in a transwell monolayer model at an Air-Liquid Interface (ALI), with multispecies deep RNA-seq. ResultsDistinct pneumococcal gene expression profiles were observed in the presence and absence of influenza. Influenza coinfection allowed for significantly greater pneumococcal growth and triggered the differential expression of bacterial genes corresponding to multiple metabolic pathways; in totality suggesting a fundamentally altered bacterial metabolic state and greater nutrient availability when coinfecting with influenza. Surprisingly, nHBEC transcriptomes were only modestly perturbed by infection with EF3030 alone in comparison to that resulting from Influenza A infection or coinfection, which had drastic alterations in thousands of genes. Influenza infected host transcriptomes suggest significant loss of ciliary function in host nHBEC cells. ConclusionsInfluenza A virus infection of nHBEC promotes pneumococcal infection. One reason for this is an altered metabolic state by the bacterium, presumably due to host components made available as result of viral infection. Influenza infection had a far greater impact on the host response than did bacterial infection alone, and this included down regulation of genes involved in expressing cilia. We conclude that influenza infection promotes a pneumococcal metabolic shift allowing for transition from colonization to disseminated disease. Author summarySecondary Streptococcus pneumoniae bacterial infections typically occur after influenza A virus respiratory infection. Such coinfections often lead to invasive pneumococcal disease. The mechanisms involved in this process are not well understood. Here, using an ex vivo human lung bronchial epithelial cell model, we investigated the biological processes of the host and pneumococcus occurring at this niche, during coinfection with multi-species transcriptomics techniques, and in vivo mouse model experimentation. We observed stark differences in global pneumococcal metabolism in different infection states, as well as viral induced epithelial cell changes in ciliary function, potentially aiding pneumococcal dissemination. Overall, this study identified broad and targeted biological processes involved in this host-pathogen interaction.

microbiology↗

bioRxiv2022

Engineered superinfective Pf phage prevents dissemination of Pseudomonas aeruginosa in a mouse burn model

Pf is a filamentous bacteriophage integrated in the chromosome of most clinical isolates of Pseudomonas aeruginosa. Under stress conditions, mutations occurring in the Pf genome result in the emergence of super-infective variants of Pf (SI-Pf) that are capable of circumventing phage immunity; therefore SI-Pf can even infect Pf-lysogenized P. aeruginosa. Herein, we identified specific mutations located between the repressor and the excisionase genes that result in the emergence of SI-Pf. Based on these findings, we genetically engineered a SI-Pf (eSI-Pf) and tested it as a phage therapy tool for the treatment of life-threatening P. aeruginosa infection of burns caused by strain PAO1. eSI-Pf was able to infect PAO1 biofilms formed in vitro on polystyrene and inhibited their formation when at high concentration. eSI-Pf also infected PAO1 present in burned skin wounds on mice but was not capable of maintaining a sustained reduction in bacterial burden beyond 24 hours. Importantly, and despite not lowering CFU/g of burn skin tissue, eSI-Pf treatment completely abolished the capability of P. aeruginosa to disseminate from the burn site to internal organs. Over the course of 10 days, this resulted in bacterial clearance and survival of all treated mice. We determined that eSI-Pf induced a small colony variant of P. aeruginosa that was unable to disseminate systemically in our burned mouse model during acute infection. Our results suggest that eSI-Pf has potential as a phage therapy against highly recalcitrant antimicrobial resistant P. aeruginosa infections of burn wounds. IMPORTANCEPseudomonas aeruginosa is a major cause of burn related infections. It is also the most likely bacterial infection to advance to sepsis and result in burn-linked death. Frequently, P. aeruginosa strains isolated from burn patients display a multidrug resistant phenotype necessitating the development of new therapeutic strategies and prophylactic treatments. In this context, phage therapy using lytic phages has demonstrated exciting potential in the control P. aeruginosa infection. However, lytic phages have a set of drawbacks during phage therapy including the induction of bacterial resistance and limited bacteria-phage interactions in vivo. Here we propose an alternative approach to interfere with P. aeruginosa pathogenesis in a burn infection model, i.e., using an engineered super-infective filamentous phage. Our study demonstrates that treatment with the engineered Pf phage can prevent sepsis and death in a burn mouse model.

microbiology↗

bioRxiv2021

Pseudomonas aeruginosa synthesizes the autoinducers of its oxylipin-dependent quorum sensing system extracellularly

The oxylipin-dependent quorum sensing system (ODS) of Pseudomonas aeruginosa relies on the production and sensing of two oxylipin autoinducers, 10S-hydroxy-(8E)-octadecenoic acid (10-HOME) and 7S,10S dihydroxy-(8E)-octadecenoic acid (7,10-DiHOME). Here, and contrary to the prevailing notion that bacterial autoinducers are synthesized intracellularly, we show that 10-HOME and 7,10-DiHOME biosynthesis occurs extracellularly, and this requires the secretion of the oxylipin synthases. We implemented a genetic screen of P. aeruginosa strain PAO1, which identified fourteen genes required for the synthesis of oxylipins. Among the identified genes, four encoded components of the ODS system and the other ten were part of the Xcp type II secretion system (T2SS). We created a deletion mutant of xcpQ, which encodes the outer membrane component of Xcp, and found it recapitulated the impaired functionality of the transposon mutants. Upon further examination, the lack of ODS function was demonstrated to be caused by the blocking of the DS enzymes secretion. Notably, the xcpQ mutant activated the ODS system when exposed to 10-HOME and 7,10-DiHOME, indicating that the sensing component of this quorum sensing system remains fully functional. In contrast with the detrimental effect previously described for T2SS in biofilm formation, here we observed that T2SS was required for robust in vitro and in vivo biofilm formation in an ODS dependent manner. To the best of our knowledge, this study is the first to find QS autoinducers that are synthetized in the extracellular space and provides new evidence for the role of the T2SS for biofilm formation in P. aeruginosa. IMPORTANCEWe previously showed that the ODS quorum sensing system of P. aeruginosa produces and responds to oxylipins derived from host oleic acid by enhancing biofilm formation and virulence. Herein, we developed a genetic screen strategy to explore the molecular basis for oxylipins synthesis and detection. Unexpectedly, we found that the ODS autoinducer synthases cross the outer membrane using the Xcp Type 2 secretion system of P. aeruginosa and thus, the biosynthesis of oxylipins occur extracellularly. Biofilm formation, which was thought to be impaired as result of Xcp activity, was found to be enhanced as result of ODS activation. This is a unique QS system strategy and reveals a new way by which P. aeruginosa interacts with the host environment.

microbiology↗

bioRxiv2021

Capsule protects against intracellular killing and enables vascular endothelial cell translocation during invasive pneumococcal disease

Streptococcus pneumoniae (Spn) is a leading cause of invasive disease. Chief among its virulence determinants is capsular polysaccharide which protects the bacterium from phagocytosis. While 100 antigenically distinct capsule types are produced by Spn, i.e. serotypes, only 20-30 are commonly associated with invasive disease. A frequency that suggests serotypespecific properties of the capsule influence virulence. Herein, we show capsule has strong antioxidant properties. Moreover, that this property promotes invasive disease by protecting Spn taken up by vascular endothelial cells during bacteremia from endosome-killing and enhancing the translocation rate into organs. Crucially, isogenic capsule-switch mutants of Spn varied considerably in their resistance to H2O2-killing in culture and measured levels correlated positively with intracellular survival rates in vitro, organ invasion rates in vivo, and epidemiologically-established human attack rates for the corresponding serotype. The amount of capsule produced and specific biochemical features of a serotype, such as acetylation, also influenced Spn resistance to oxidative stress. Autolysin-mediated shedding was also found to be necessary, indicating that capsule worked as a distal sink for reactive oxygen species. Our results outline a new role for capsular polysaccharide, as an intracellular antioxidant. They help to explain why certain serotypes of Spn have greater propensity for human disease.

microbiology↗

bioRxiv2020

Influenza-induced oxidative stress sensitizes lung cells to bacterial toxin-mediated necroptosis

RationalePneumonia caused by Influenza A virus (IAV) co- and secondary bacterial infections are characterized by their severity. Previously we have shown that pore-forming toxin (PFT)-mediated necroptosis is a key driver of acute lung injury during bacterial pneumonia. Here, we evaluate the impact of IAV on PFT-induced acute lung injury during co- and secondary Streptococcus pneumoniae (Spn) infection. ObjectivesDetermine the impact of IAV infection on bacterial PFT-mediated lung epithelial cell (LEC) necroptosis. Determine the molecular basis for increased sensitivity and if inhibition of necroptosis or oxidative stress blocks IAV sensitization of LEC to PFT. MethodsMice and cells were challenged with IAV followed by Spn. Necroptosis was monitored by measuring cell death at fixed time points post-infection and immunofluorescent detection of necroptosis. Wildtype mice and LEC were treated with necroptosis inhibitors. Necroptosis effector molecule MLKL deficiency was tested for infection synergy. Oxidative damage to DNA and lipids as result of infection was measured in vitro and in vivo. Necroptosis and anti-oxidant therapy efficacy to reduce disease severity was tested in vivo. Measurements and Main ResultsIAV synergistically sensitized LEC for PFT-mediated necroptosis in vitro and in murine models of Spn co-infection and secondary infection. Pharmacological induction of oxidative stress sans virus sensitized cells for PFT-mediated necroptosis. Necroptosis inhibition reduced disease severity during secondary bacterial infection. ConclusionsIAV-induced oxidative stress sensitizes LEC for PFT-mediated necroptosis. This is a new molecular explanation for severe influenza-associated bacterial infections. Necroptosis inhibitors are potential therapeutic strategies to reduce IAV-primed bacterial pneumonia severity. SummaryHere we demonstrate that Influenza A virus (IAV) infection synergistically sensitizes lung cells to bacterial pore-forming toxin (PFT)-mediated necroptosis. Moreover, this contributes to the severity of lung injury that is observed during co- and secondary infection with Streptococcus pneumoniae. IAV-induced oxidative stress was identified as a key factor contributing to cell sensitization and induction of oxidative stress sans virus was sufficient to synergistically enhance susceptibility to PFT-mediated killing. Our results advance our understanding on the molecular basis of co- and secondary bacterial infection to influenza and identifies necroptosis inhibition and antioxidant therapy as potential intervention strategies.

microbiology↗