scholarly journals Children with Invasive Staphylococcus aureus Disease Exhibit a Potently Neutralizing Antibody Response to the Cytotoxin LukAB

2013 ◽  
Vol 82 (3) ◽  
pp. 1234-1242 ◽  
Author(s):  
Isaac P. Thomsen ◽  
Ashley L. DuMont ◽  
David B. A James ◽  
Pauline Yoong ◽  
Benjamin R. Saville ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Antibody Response ◽  
High Titer ◽  
Humoral Response ◽  
Neutralizing Antibody ◽  
Human Neutrophils ◽  
Serum Samples ◽  
Marked Rise ◽  
Content Type

ABSTRACTDespite the importance ofStaphylococcus aureusas a common invasive bacterial pathogen, the humoral response to infection remains inadequately defined, particularly in children. The purpose of this study was to assess the humoral response to extracellular staphylococcal virulence factors, including the bicomponent leukotoxins, which are critical for the cytotoxicity ofS. aureustoward human neutrophils. Children with culture-provenS. aureusinfection were prospectively enrolled and stratified by disease type. Fifty-three children were enrolled in the study, of which 90% had invasive disease. Serum samples were obtained during the acute (within 48 h) and convalescent (4 to 6 weeks postinfection) phases, at which point both IgG titers againstS. aureusexotoxins were determined, and the functionality of the generated antibodies was evaluated. Molecular characterization of clinical isolates was also performed. We observed a marked rise in antibody titer from acute-phase to convalescent-phase sera for LukAB, the most recently describedS. aureusbicomponent leukotoxin. LukAB production by the isolates was strongly correlated with cytotoxicityin vitro, and sera containing anti-LukAB antibodies potently neutralized cytotoxicity. Antibodies toS. aureusantigens were detectable in healthy pediatric controls but at much lower titers than in sera from infected subjects. The discovery of a high-titer, neutralizing antibody response to LukAB during invasive infections suggests that this toxin is producedin vivoand that it elicits a functional humoral response.

scholarly journals Three-Dimensional In Vitro Staphylococcus aureus Abscess Communities Display Antibiotic Tolerance and Protection from Neutrophil Clearance

2020 ◽  
Vol 88 (11) ◽  
Author(s):  
Marloes I. Hofstee ◽  
Martijn Riool ◽  
Igors Terjajevs ◽  
Keith Thompson ◽  
Martin J. Stoddart ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Immune Cells ◽  
Early Stage ◽  
Three Dimensional ◽  
Collagen Gel ◽  
Maximum Size ◽  
Human Neutrophils ◽  
Content Type

ABSTRACT Staphylococcus aureus is a prominent human pathogen in bone and soft-tissue infections. Pathophysiology involves abscess formation, which consists of central staphylococcal abscess communities (SACs), surrounded by a fibrin pseudocapsule and infiltrating immune cells. Protection against the ingress of immune cells such as neutrophils, or tolerance to antibiotics, remains largely unknown for SACs and is limited by the lack of availability of in vitro models. We describe a three-dimensional in vitro model of SACs grown in a human plasma-supplemented collagen gel. The in vitro SACs reached their maximum size by 24 h and elaborated a fibrin pseudocapsule, as confirmed by electron and immunofluorescence microscopy. The in vitro SACs tolerated 100× the MIC of gentamicin alone and in combination with rifampin, while planktonic controls and mechanically dispersed SACs were efficiently killed. To simulate a host response, SACs were exposed to differentiated PLB-985 neutrophil-like (dPLB) cells and to primary human neutrophils at an early stage of SAC formation or after maturation at 24 h. Both cell types were unable to clear mature in vitro SACs, but dPLB cells prevented SAC growth upon early exposure before pseudocapsule maturation. Neutrophil exposure after plasmin pretreatment of the SACs resulted in a significant decrease in the number of bacteria within the SACs. The in vitro SAC model mimics key in vivo features, offers a new tool to study host-pathogen interactions and drug efficacy assessment, and has revealed the functionality of the S. aureus pseudocapsule in protecting the bacteria from host phagocytic responses and antibiotics.

scholarly journals Bovine Staphylococcus aureus Secretes the Leukocidin LukMF′ To Kill Migrating Neutrophils through CCR1

mBio ◽  
2015 ◽  
Vol 6 (3) ◽  
Author(s):  
M. Vrieling ◽  
K. J. Koymans ◽  
D. A. C. Heesterbeek ◽  
P. C. Aerts ◽  
V. P. M. G. Rutten ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Host Specificity ◽  
Ex Vivo ◽  
Field Isolate ◽  
Human Neutrophils ◽  
Fibrin Gel ◽  
Content Type ◽  
New Targets ◽  
Bovine Neutrophils

ABSTRACTAlthoughStaphylococcus aureusis best known for infecting humans, bovine-specific strains are a major cause of mastitis in dairy cattle. The bicomponent leukocidin LukMF′, exclusively harbored byS. aureusof ruminant origin, is a virulence factor associated with bovine infections. In this study, the molecular basis of the host specificity of LukMF′ is elucidated by identification of chemokine receptor CCR1 as its target. Bovine neutrophils, the major effector cells in the defense against staphylococci, express significant cell surface levels of CCR1, whereas human neutrophils do not. This causes the particular susceptibility of bovine neutrophils to pore formation induced by LukMF′. BovineS. aureusstrains produce high levels of LukMF′in vitro. In culture supernatant of the mastitis field isolate S1444, LukMF′ was the most important cytotoxic agent for bovine neutrophils. In a fibrin gel matrix, the effects of thein situsecreted toxins on neutrophils migrating towardS. aureuswere visualized. Under these physiologicalex vivoconditions, bovineS. aureusS1444 efficiently killed approaching neutrophils at a distance through secretion of LukMF′. Altogether, our findings illustrate the coevolution of pathogen and host, provide new targets for therapeutic and vaccine approaches to treat staphylococcal diseases in the cow, and emphasize the importance of staphylococcal toxins in general.IMPORTANCEThis study explains the mechanism of action of LukMF′, a bicomponent toxin found in bovine lineages ofS. aureusthat is associated with mastitis in cattle. At a molecular level, we describe how LukMF′ can specifically kill bovine neutrophils. Here, we demonstrate the contribution of toxins in the determination of host specificity and contribute to the understanding of mechanisms of coevolution of pathogen and host. Our study provides new targets that can be used in therapeutic and vaccine approaches to treat staphylococcal diseases in the cow. We also demonstrate the importance of toxins in specific elimination of immune cells, which has broader implications, especially in human infections.

scholarly journals Direct Microscopic Observation of Human Neutrophil-Staphylococcus aureus Interaction In Vitro Suggests a Potential Mechanism for Initiation of Biofilm Infection on an Implanted Medical Device

2019 ◽  
Vol 87 (12) ◽  
Author(s):  
Niranjan Ghimire ◽  
Brian A. Pettygrove ◽  
Kyler B. Pallister ◽  
James Stangeland ◽  
Shelby Stanhope ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Head Start ◽  
Bacterial Growth ◽  
Bacterial Biomass ◽  
Bacterial Biofilm ◽  
Confocal Scanning Laser Microscopy ◽  
Human Neutrophils ◽  
Content Type ◽  
Biofilm Infection

ABSTRACT The ability of human neutrophils to clear newly attached Staphylococcus aureus bacteria from a serum-coated glass surface was examined in vitro using time-lapse confocal scanning laser microscopy. Quantitative image analysis was used to measure the temporal change in bacterial biomass, neutrophil motility, and fraction of the surface area policed by neutrophils. In control experiments in which the surface was inoculated with bacteria but no neutrophils were added, prolific bacterial growth was observed. Neutrophils were able to control bacterial growth but only consistently when the neutrophil/bacterium number ratio exceeded approximately 1. When preattached bacteria were given a head start and allowed to grow for 3 h prior to neutrophil addition, neutrophils were unable to maintain control of the nascent biofilm. In these head-start experiments, aggregates of bacterial biofilm with areas of 50 μm2 or larger formed, and the growth of such aggregates continued even when multiple neutrophils attacked a cluster. These results suggest a model for the initiation of a biofilm infection in which a delay in neutrophil recruitment to an abiotic surface allows surface-attached bacteria time to grow and form aggregates that become protected from neutrophil clearance. Results from a computational model of the neutrophil-biofilm surface contest supported this conceptual model and highlighted the stochastic nature of the interaction. Additionally, we observed that both neutrophil motility and clearance of bacteria were impaired when oxygen tension was reduced to 0% or 2% O2.

scholarly journals Evaluation of the Borrelia burgdorferi BBA64 Protein as a Protective Immunogen in Mice

2014 ◽  
Vol 21 (4) ◽  
pp. 526-533 ◽  
Author(s):  
Kevin S. Brandt ◽  
Toni G. Patton ◽  
Anna S. Allard ◽  
Melissa J. Caimano ◽  
Justin D. Radolf ◽  
...  
Keyword(s):  
Borrelia Burgdorferi ◽  
Antibody Response ◽  
Lyme Borreliosis ◽  
Protective Immunity ◽  
High Titer ◽  
Passive Immunization ◽  
Inbred Strains ◽  
Tick Bite ◽  
Content Type

ABSTRACTTheBorrelia burgdorferibba64gene product is a surface-localized lipoprotein synthesized within mammalian and tick hosts and is involved in vector transmission of disease. These properties suggest that BBA64 may be a vaccine candidate against Lyme borreliosis. In this study, protective immunity againstB. burgdorferichallenge was assessed in mice immunized with the BBA64 protein. Mice developed a high-titer antibody response following immunization with soluble recombinant BBA64 but were not protected when challenged by needle inoculation of culture-grown spirochetes. Likewise, mice passively immunized with an anti-BBA64 monoclonal antibody were not protected against needle-inoculated organisms. BBA64-immunized mice were subjected toB. burgdorferichallenge by the natural route of a tick bite, but these trials did not demonstrate significant protective immunity in either outbred or inbred strains of mice. Lipidated recombinant BBA64 produced inEscherichia coliwas assessed for possible improved elicitation of a protective immune response. Although inoculation with this antigen produced a high-titer antibody response, the lipidated BBA64 also was unsuccessful in protecting mice fromB. burgdorferichallenge by tick bites. Anti-BBA64 antibodies raised in rats eradicated the organisms, as evidenced byin vitroborreliacidal assays, thus demonstrating the potential for BBA64 to be effective as a protective immunogen. However, passive immunization with the same monospecific rat anti-BBA64 polyclonal serum failed to provide protection against tick bite-administered challenge. These results reveal the challenges faced in not only identifyingB. burgdorferiproteins with potential protective capability but also in producing recombinant antigens conducive to preventive therapies against Lyme borreliosis.

scholarly journals Characterization of Alpha-ToxinhlaGene Variants, Alpha-Toxin Expression Levels, and Levels of Antibody to Alpha-Toxin in Hemodialysis and Postsurgical Patients with Staphylococcus aureus Bacteremia

2014 ◽  
Vol 53 (1) ◽  
pp. 227-236 ◽  
Author(s):  
Batu K. Sharma-Kuinkel ◽  
Yuling Wu ◽  
David E. Tabor ◽  
Hoyin Mok ◽  
Bret R. Sellman ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Monoclonal Antibody ◽  
Clinical Outcome ◽  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Enzyme Linked Immunosorbent Assay ◽  
Alpha Toxin ◽  
Content Type ◽  
Antibody Levels

Alpha-toxin is a majorStaphylococcus aureusvirulence factor. This study evaluated potential relationships betweenin vitroalpha-toxin expression ofS. aureusbloodstream isolates, anti-alpha-toxin antibody in serum of patients withS. aureusbacteremia (SAB), and clinical outcomes in 100 hemodialysis and 100 postsurgical SAB patients. Isolates underwentspatyping andhlasequencing. Serum anti-alpha-toxin IgG and neutralizing antibody levels were measured by using an enzyme-linked immunosorbent assay and a red blood cell (RBC)-based hemolysis neutralization assay. Neutralization of alpha-toxin by an anti-alpha-toxin monoclonal antibody (MAb MEDI4893) was tested in an RBC-based lysis assay. Most isolates encodedhla(197/200; 98.5%) and expressed alpha-toxin (173/200; 86.5%).In vitroalpha-toxin levels were inversely associated with survival (cure, 2.19 μg/ml, versus failure, 1.09 μg/ml;P< 0.01). Both neutralizing (hemodialysis, 1.26 IU/ml, versus postsurgical, 0.95;P< 0.05) and IgG (hemodialysis, 1.94 IU/ml, versus postsurgical, 1.27;P< 0.05) antibody levels were higher in the hemodialysis population. Antibody levels were also significantly higher in patients infected with alpha-toxin-expressingS. aureusisolates (P< 0.05). Levels of both neutralizing antibodies and IgG were similar among patients who were cured and those not cured (failures). Sequence analysis ofhlarevealed 12 distincthlagenotypes, and all genotypic variants were susceptible to a neutralizing monoclonal antibody in clinical development (MEDI4893). These data demonstrate that alpha-toxin is highly conserved in clinicalS. aureusisolates. Higherin vitroalpha-toxin levels were associated with a positive clinical outcome. Although patients infected with alpha-toxin-producingS. aureusexhibited higher anti-alpha-toxin antibody levels, these levels were not associated with a better clinical outcome in this study.

scholarly journals Staphylococcus aureus Elaborates Leukocidin AB To Mediate Escape from within Human Neutrophils

2013 ◽  
Vol 81 (5) ◽  
pp. 1830-1841 ◽  
Author(s):  
Ashley L. DuMont ◽  
Pauline Yoong ◽  
Bas G. J. Surewaard ◽  
Meredith A. Benson ◽  
Reindert Nijland ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Polymorphonuclear Leukocytes ◽  
The United States ◽  
Growth Conditions ◽  
Human Neutrophils ◽  
Cytotoxic Potential ◽  
Content Type ◽  
Human Pmns ◽  
Mrsa Strains

ABSTRACTMethicillin-resistantStaphylococcus aureus(MRSA) strains of the pulsed-field type USA300 are primarily responsible for the current community-associated epidemic of MRSA infections in the United States. The success of USA300 is partly attributed to the ability of the pathogen to avoid destruction by human neutrophils (polymorphonuclear leukocytes [PMNs]), which are crucial to the host immune response toS. aureusinfection. In this work, we investigated the contribution of bicomponent pore-forming toxins to the ability of USA300 to withstand attack from primary human PMNs. We demonstrate thatin vitrogrowth conditions influence the expression, production, and availability of leukotoxins by USA300, which in turn impact the cytotoxic potential of this clone toward PMNs. Interestingly, we also found that upon exposure to PMNs, USA300 preferentially activates the promoter of thelukABoperon, which encodes the recently identified leukocidin AB (LukAB). LukAB elaborated by extracellularS. aureusforms pores in the plasma membrane of PMNs, leading to PMN lysis, highlighting a contribution of LukAB to USA300 virulence. We now show that LukAB also facilitates the escape of bacteria engulfed within PMNs, in turn enabling the replication and outgrowth ofS. aureus. Together, these results suggest that upon encountering PMNsS. aureusinduces the production of LukAB, which serves as an extra- and intracellular weapon to protect the bacterium from destruction by human PMNs.

scholarly journals Human Immune Proteome in Experimental Colonization with Staphylococcus aureus

2009 ◽  
Vol 16 (11) ◽  
pp. 1607-1614 ◽  
Author(s):  
Silva Holtfreter ◽  
Thi Thu Hoai Nguyen ◽  
Heiman Wertheim ◽  
Leif Steil ◽  
Harald Kusch ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Antibody Response ◽  
Adaptive Immune System ◽  
Humoral Response ◽  
Neutralizing Antibody ◽  
Protective Role ◽  
Extracellular Proteins ◽  
Nasal Colonization ◽  
Igg Antibody ◽  
Alpha Hemolysin

ABSTRACT More than 20% of adults are persistently colonized with Staphylococcus aureus. When hospitalized, these carriers have increased risks of infection with their own strains. However, a recent study demonstrated a lower incidence of bacteremia-related death among carriers than among noncarriers, raising the question whether the adaptive immune system plays a protective role. In fact, S. aureus carriers mount a highly specific neutralizing antibody response against superantigens of their colonizing strains. We now used 2-dimensional immunoblotting to investigate the profiles of antibodies from healthy individuals against S. aureus extracellular proteins. Moreover, we tested whether symptom-free experimental colonization of these individuals with an S. aureus strain of low virulence, 8325-4, is sufficient to induce an antibody response. Sera obtained before and 4 weeks after colonization were screened for immunoglobulin G (IgG) antibody binding to extracellular staphylococcal proteins. At baseline, most volunteers harbored IgG directed against conserved virulence factors, including alpha-hemolysin (Hla), beta-hemolysin (Hlb), phospholipase C (Plc), staphylococcal serine protease (SspA), and cysteine protease (SspB). However, the variability of spot patterns and intensities was striking and could be important in case of infection. Experimental nasal colonization with S. aureus 8325-4 did not elicit new antibodies or boost the humoral response. Thus, the high antibody prevalence in humans is likely not induced by short-term nasal colonization, and presumably minor infections are required to trigger anti-S. aureus antibody responses.

scholarly journals Seroprevalence of Anti-SARS-CoV-2 IgG and IgM among Adults over 65 Years Old in the South of Italy

Diagnostics ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 483
Author(s):  
Immacolata Polvere ◽  
Alfredina Parrella ◽  
Giovanna Casamassa ◽  
Silvia D’Andrea ◽  
Annamaria Tizzano ◽  
...  
Keyword(s):  
Antibody Response ◽  
Immunoglobulin M ◽  
Molecular Testing ◽  
Elisa Assay ◽  
The South ◽  
Serum Samples ◽  
Serological Screening ◽  
Rna Detection ◽  
In Vitro Diagnostic

SARS-CoV-2 is a zoonotic betacoronavirus associated with worldwide transmission of COVID-19 disease. By the beginning of March, WHO reported about 113,820,000 confirmed cases including more than 2,527,000 deaths all over the world. However, the true extent of virus circulation or its real infection/fatality ratio is not well-estimated due to the huge portion of asymptomatic infections. In this observational study, we have estimated the prevalence of specific immunoglobulin M and G directed towards SARS-CoV-2 antigen in a cohort of 1383 adult volunteers aged over 65 years old, living in the district of Benevento, in the South of Italy. Serological screening was carried out on capillary blood in September 2020, seven months after pandemic outbreak in Italy, to evaluate virus circulation and antibody response among elderly adults, in which severe symptoms due to viral infection are more common. The overall seroprevalence of anti-SARS-CoV-2 antibodies was 4.70% (CI 3.70%–5.95%) with no statistically significant differences between sexes. Among these, 69.69% (CI 55.61%–77.80%) tested positive to IgM, 23.08% (CI 14.51%–34.64%) to IgG and 9.23% (CI 4.30%–18.71%) was positive for both. All patients that were positive to IgM underwent molecular testing through RT-qPCR on oral-rhino pharyngeal swabs and only one specimen was positive for SARS-CoV-2 RNA detection. Instead, the presence of IgG from screened volunteers was confirmed by re-testing serum samples using both an ELISA assay validated for in vitro diagnostic use (IVD) and a recently published synthetic peptide-based ELISA assay. In conclusion, our report suggests that (1) early restrictions were successful in limiting COVID-19 diffusion in the district of Benevento; (2) rapid serological analysis is an ideal testing for both determining real seroprevalence and massive screening, whereas detection of viral RNA remains a gold standard for identification of infected patients; (3) even among people without COVID-19 related symptoms, the antibody response against SARS-CoV-2 antigens has individual features.

scholarly journals A longitudinal study of SARS-CoV-2-infected patients reveals a high correlation between neutralizing antibodies and COVID-19 severity

2021 ◽  
Author(s):  
Vincent Legros ◽  
Solène Denolly ◽  
Manon Vogrig ◽  
Bertrand Boson ◽  
Eglantine Siret ◽  
...  
Keyword(s):  
Intensive Care ◽  
Neutralizing Antibodies ◽  
Vaccine Development ◽  
Surface Protein ◽  
Humoral Response ◽  
Neutralizing Antibody ◽  
Rapid Decline ◽  
Serum Samples ◽  
Immune Correlates ◽  
Human Coronaviruses

AbstractUnderstanding the immune responses elicited by SARS-CoV-2 infection is critical in terms of protection against reinfection and, thus, for public health policy and vaccine development for COVID-19. In this study, using either live SARS-CoV-2 particles or retroviruses pseudotyped with the SARS-CoV-2 S viral surface protein (Spike), we studied the neutralizing antibody (nAb) response in serum samples from a cohort of 140 SARS-CoV-2 qPCR-confirmed infections, including patients with mild symptoms and also more severe forms, including those that required intensive care. We show that nAb titers correlated strongly with disease severity and with anti-spike IgG levels. Indeed, patients from intensive care units exhibited high nAb titers; conversely, patients with milder disease symptoms had heterogeneous nAb titers, and asymptomatic or exclusive outpatient-care patients had no or low nAbs. We found that nAb activity in SARS-CoV-2-infected patients displayed a relatively rapid decline after recovery compared to individuals infected with other coronaviruses. Moreover, we found an absence of cross-neutralization between endemic coronaviruses and SARS-CoV-2, indicating that previous infection by human coronaviruses may not generate protective nAbs against SARS-CoV-2. Finally, we found that the D614G mutation in the spike protein, which has recently been identified as the current major variant in Europe, does not allow neutralization escape. Altogether, our results contribute to our understanding of the immune correlates of SARS-CoV-2-induced disease, and rapid evaluation of the role of the humoral response in the pathogenesis of SARS-CoV-2 is warranted.

scholarly journals Exogenous Alginate Protects Staphylococcus aureus from Killing by Pseudomonas aeruginosa

2019 ◽  
Vol 202 (8) ◽  
Author(s):  
Courtney E. Price ◽  
Dustin G. Brown ◽  
Dominique H. Limoli ◽  
Vanessa V. Phelan ◽  
George A. O’Toole
Keyword(s):  
Staphylococcus Aureus ◽  
Pseudomonas Aeruginosa ◽  
Physical Space ◽  
Late Time ◽  
Protective Effects ◽  
Content Type ◽  
Alginate Production ◽  
The Impact

ABSTRACT Cystic fibrosis (CF) patients chronically infected with both Pseudomonas aeruginosa and Staphylococcus aureus have worse health outcomes than patients who are monoinfected with either P. aeruginosa or S. aureus. We showed previously that mucoid strains of P. aeruginosa can coexist with S. aureus in vitro due to the transcriptional downregulation of several toxic exoproducts typically produced by P. aeruginosa, including siderophores, rhamnolipids, and HQNO (2-heptyl-4-hydroxyquinoline N-oxide). Here, we demonstrate that exogenous alginate protects S. aureus from P. aeruginosa in both planktonic and biofilm coculture models under a variety of nutritional conditions. S. aureus protection in the presence of exogenous alginate is due to the transcriptional downregulation of pvdA, a gene required for the production of the iron-scavenging siderophore pyoverdine as well as the downregulation of the PQS (Pseudomonas quinolone signal) (2-heptyl-3,4-dihydroxyquinoline) quorum sensing system. The impact of exogenous alginate is independent of endogenous alginate production. We further demonstrate that coculture of mucoid P. aeruginosa with nonmucoid P. aeruginosa strains can mitigate the killing of S. aureus by the nonmucoid strain of P. aeruginosa, indicating that the mechanism that we describe here may function in vivo in the context of mixed infections. Finally, we investigated a panel of mucoid clinical isolates that retain the ability to kill S. aureus at late time points and show that each strain has a unique expression profile, indicating that mucoid isolates can overcome the S. aureus-protective effects of mucoidy in a strain-specific manner. IMPORTANCE CF patients are chronically infected by polymicrobial communities. The two dominant bacterial pathogens that infect the lungs of CF patients are P. aeruginosa and S. aureus, with ∼30% of patients coinfected by both species. Such coinfected individuals have worse outcomes than monoinfected patients, and both species persist within the same physical space. A variety of host and environmental factors have been demonstrated to promote P. aeruginosa-S. aureus coexistence, despite evidence that P. aeruginosa kills S. aureus when these organisms are cocultured in vitro. Thus, a better understanding of P. aeruginosa-S. aureus interactions, particularly mechanisms by which these microorganisms are able to coexist in proximal physical space, will lead to better-informed treatments for chronic polymicrobial infections.

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