Complement susceptibility in relation to genome sequence of Klebsiella pneumoniae from Thai hospitals

Loraine, Jessica; Heinz, Eva; Almeida, Jessica De Sousa; Milevskyy, Oleksandr; Voravuthikunchai, Supayang Piyawan; Srimanote, Potjanee; Kiratisin, Pattarachai; Thomson, Nicholas R.; Taylor, Peter W.

doi:10.1016/j.molimm.2018.06.148

Cited by 3 publications

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“…Bacteria CFUs were quantified after incubation with active or heat-inactivated serum at 37°C for 1 h. The result showed that YBQ strain exhibited moderate susceptibility with 41% of complement-mediated killing, while strain 700721 showed higher susceptible to complement-mediated killing (73%, Figure 4 ). This result illustrated that the complement pathway was an important route to clear the bacteria in the blood, which may be essential for alleviating the septicemia, and the virulence of different strains may impact the serum complement susceptibility, which was inconsistent with the result reported previously [ 35 ].…”

Section: Resultscontrasting

confidence: 97%

Innate Immune Effectors Play Essential Roles in Acute Respiratory Infection Caused by Klebsiella pneumoniae

Liu

Chen

Yuan

et al. 2020

Journal of Immunology Research

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Innate immune effectors constitute the first line of host defense against pathogens. However, the roles of these effectors are not clearly defined during Klebsiella pneumoniae (K. pneumoniae) respiratory infection. In the current study, we established an acute pneumonia model of K. pneumoniae respiratory infection in mice and confirmed that the injury was most severe 48 h post infection. Flow cytometric assay demonstrated that alveolar macrophages were the predominant cells in BALF before infection, and neutrophils were quickly recruited after infection, and this was in consistent with the kinetics of chemokine expression. Further, we depleted neutrophils, macrophages, and complement pathways in vivo and challenged these mice with a sublethal dose of K. pneumonia, the result showed that 80%, 60%, and 40% of mice were died in these groups, respectively, while no deaths occurred in the control group. Besides, innate immune effector depleted mice showed higher bacterial burdens in lungs and blood, companied with more severe lung damage and increased levels of cytokine/chemokine expression. These results demonstrated that the innate immune effectors are critical in the early controlling of K. pneumoniae infection, and neutrophils are the most important. Thus, alternative strategies targeting these innate immune effectors may be effective in controlling of K. pneumoniae respiratory infection.

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Section: Resultscontrasting

confidence: 97%

Innate Immune Effectors Play Essential Roles in Acute Respiratory Infection Caused by Klebsiella pneumoniae

Liu

Chen

Yuan

et al. 2020

Journal of Immunology Research

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“…complement-resistant bacteria may not only mask their cell surface from the initial recognition by the three complement pathways but may also inhibit later stages of the complement pathway by altering their surface configuration in response to envelope stress, preventing membrane insertion and MAC pore formation. Our findings that distinct K. pneumoniae strains can have distinct complement evasion mechanisms, underpinned by dramatically different gene sets, highlights the complexity associated with predicting serum resistance based on genome sequence or single virulence factors—an undertaking which is not yet possible for K. pneumoniae ( 27 ). A comprehensive understanding of the basis of complement resistance in Gram-negative bacteria will only be forthcoming when the behavior of such clinically relevant pathogens can be explained.…”

Section: Discussionmentioning

confidence: 95%

“…Resistance to killing by complement is an important yet incompletely understood feature of K. pneumoniae pathogenesis ( 4 , 8 , 27 ). The prominent polysaccharide capsule has been invoked as a key determinant of resistance by virtue of its capacity to limit C3b deposition or assembly of the membrane attack complex ( 8 , 26 ), but it is clear that other factors also contribute to the complement-resistant phenotype ( 27 ). Resistance to serum killing is associated with K. pneumoniae hypervirulence, and we therefore selected three well-studied hypervirulent strains, as well as a recently isolated clinical strain, for our analyses.…”

Section: Discussionmentioning

confidence: 99%

“…Multiple different factors can influence serum resistance in K. pneumoniae , including capsule type and amount, O-antigen type, and various surface proteins; capsules and O antigens have each been invoked as the main determinant of complement resistance ( 9 , 26 ). However, a recent study of >150 K. pneumoniae clinical isolates from Thailand with various complement susceptibilities concluded that susceptibility did not correlate with the presence of specific genes, particular capsule types, or even with the hypercapsulation phenotype of the isolates ( 27 ). This study highlighted the main limitation of collective studies on complement resistance in K. pneumoniae to date—that although many resistance factors are individually well characterized, there is very limited understanding of how their activities play out in different combinations or across diverse isolates of K. pneumoniae .…”

Section: Introductionmentioning

confidence: 99%

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Genomic Profiling Reveals Distinct Routes To Complement Resistance in Klebsiella pneumoniae

et al. 2020

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The serum complement system is a first line of defense against bacterial invaders. Resistance to killing by serum enhances the capacity of Klebsiella pneumoniae to cause infection, but it is an incompletely understood virulence trait. Identifying and characterizing the factors responsible for preventing activation of, and killing by, serum complement could inform new approaches to treatment of K. pneumoniae infections. Here, we used functional genomic profiling to define the genetic basis of complement resistance in four diverse serum-resistant K. pneumoniae strains (NTUH-K2044, B5055, ATCC 43816, and RH201207), and explored their recognition by key complement components. More than 90 genes contributed to resistance in one or more strains, but only three, rfaH, lpp, and arnD, were common to all four strains. Deletion of the antiterminator rfaH, which controls the expression of capsule and O side chains, resulted in dramatic complement resistance reductions in all strains. The murein lipoprotein gene lpp promoted capsule retention through a mechanism dependent on its C-terminal lysine residue; its deletion led to modest reductions in complement resistance. Binding experiments with the complement components C3b and C5b-9 showed that the underlying mechanism of evasion varied in the four strains: B5055 and NTUH-K2044 appeared to bypass recognition by complement entirely, while ATCC 43816 and RH201207 were able to resist killing despite being associated with substantial levels of C5b-9. All rfaH and lpp mutants bound C3b and C5b-9 in large quantities. Our findings show that, even among this small selection of isolates, K. pneumoniae adopts differing mechanisms and utilizes distinct gene sets to avoid complement attack.

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“…For example, deletion of rfaH decreased capsule uronic acid production, increased complement C3b and MAC protein complex binding, and increased serum killing in a reference CR-Kp isolate called RH-201207 ( 67 ). The importance of the CPS in MDR-Kp fitness is further bolstered by a recent report that 64% of CR-Kp clinical isolates were able to persist in human serum, though they did not demonstrate the rapid growth that is typical of hvKp strains ( 78 , 79 ). A more complete understanding of the role of CPS production and modulation in MDR-Kp is necessary to advance therapeutic strategies to limit the significant mortality associated with MDR-Kp infection in humans.…”

Section: Complement Evasion and Serum Resistance In Hvkp Versus Mdr-kpmentioning

confidence: 99%

Finding Order in the Chaos: Outstanding Questions in Klebsiella pneumoniae Pathogenesis

et al. 2021

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Klebsiella pneumoniae are gram-negative facultative anaerobes that are found within host-associated commensal microbiomes, but they can also cause a wide range of infections that are often difficult to treat. These infections are caused by different pathotypes of K. pneumoniae, called either classical and hypervirulent strains. These two strain groups are genetically distinct, inhabit non-overlapping geographies, and cause different types of harmful infections in humans. These distinct bacterial groups have also been found to interact differently with the host immune system. Initial innate immune defenses against K. pneumoniae infection include complement, macrophages, neutrophils, and monocytes; these defenses are primary strategies employed by the host to clear infections. K. pneumoniae pathogenesis depends upon the interactions between the microbe and each of these host defenses, and it is becoming increasingly apparent that bacterial genetic diversity impacts the outcomes of these interactions. Herein we highlight recent advances in our understanding of K. pneumoniae pathogenesis, with a focus on how bacterial evolution and diversity impact K. pneumoniae interactions with mammalian innate immune host defenses. We also discuss outstanding questions regarding how K. pneumoniae can frustrate normal immune responses, capitalize upon states of immunocompromise, and cause infections with high mortality.

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Complement susceptibility in relation to genome sequence of Klebsiella pneumoniae from Thai hospitals

Cited by 3 publications

References 0 publications

Innate Immune Effectors Play Essential Roles in Acute Respiratory Infection Caused by Klebsiella pneumoniae

Innate Immune Effectors Play Essential Roles in Acute Respiratory Infection Caused by Klebsiella pneumoniae

Genomic Profiling Reveals Distinct Routes To Complement Resistance in Klebsiella pneumoniae

Finding Order in the Chaos: Outstanding Questions in Klebsiella pneumoniae Pathogenesis

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