outer membrane remodeling: role in resistance to host innate immunity

Ernst, Robert K.; Guina, Tína; Miller, Samuel I.

doi:10.1016/s1286-4579(01)01494-0

Cited by 217 publications

(221 citation statements)

References 51 publications

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“…It has also become apparent that bacterial stratagems to evade these host defense molecules frequently take the form of mutations or programmed responses that reduce the negative charges of molecules displayed on the microbial surface or in its membrane bilayer(s) (13)(14)(15)(16). HIV-1 was not highly successful in overcoming the effects of RC-101, increasing its resistance by only 5-to 10-fold.…”

Section: Discussionmentioning

confidence: 99%

“…2 and 3). Bacteria can acquire resistance to cationic antimicrobial peptides via genetic or regulatory responses that decrease the negative charge of their membrane phospholipids, teichoic acids, or regions of their LPS (13)(14)(15)(16). Enveloped viruses, such as HIV-1, HSV-1, and HSV-2, are believed to be susceptible to RCs, because their net positive charge and lectinlike behavior permit binding to anionic or carbohydrate-containing viral or host cell membrane domains, including sites implicated in membrane fusion and viral uptake (7,9,17,18).…”

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confidence: 99%

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HIV-1 Adapts to a Retrocyclin with Cationic Amino Acid Substitutions That Reduce Fusion Efficiency of gp41

Cole¹,

Yang

Warren³

et al. 2006

The Journal of Immunology

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Retrocyclin (RC)-101 is a cationic θ-defensin that inhibits HIV-1 entry. Passaging HIV-1BAL under selective pressure by this cyclic minidefensin resulted in only a 5- to 10-fold decrease in viral susceptibility to RC-101. Emergent viral isolates had three amino acid substitutions in their envelope glycoprotein. One was in a CD4-binding region of gp120, and the others were in the heptad repeat (HR) domains of gp41 (HR1 and HR2). Each mutation replaced an electroneutral or electronegative residue with one that was positively charged. These mutations were evaluated either alone or in combination in a single-round viral entry assay. Although the mutation in gp120 did not affect viral entry, the mutation in HR1 of gp41 conferred relative resistance to RC-101. Interestingly, the envelope with the HR2 mutation was less efficient and became codependent on the presence of RC-101 for entry. The adaptive response of HIV-1 to this cationic host defense peptide resembles the responses of bacteria that modulate their surface or membrane charge to evade analogous host defense peptides. These findings also suggest that interactions between θ-defensins and gp41 may contribute to the ability of these cyclic minidefensins to prevent HIV-1 entry into target cells.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

HIV-1 Adapts to a Retrocyclin with Cationic Amino Acid Substitutions That Reduce Fusion Efficiency of gp41

Cole¹,

Yang

Warren³

et al. 2006

The Journal of Immunology

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“…Some bacterial pathogens, such as Salmonella enterica serovar Typhimurium are able to establish a persistent infection in the intestine of C. elegans, reducing the life span of the host. Several genes needed for virulence in mammals are also required for pathogenesis in C. elegans (2,10,16,28), implying that the invasion and proliferation of serovar Typhimurium in the host intestine depend on mechanisms common to the nematode and mammals. This makes C. elegans a relevant model for determining the infectivity and fitness of antibiotic-resistant bacteria during a host infection.…”

mentioning

confidence: 99%

“…For example, mutations in the genes fur-1, ompR, or rpoS involved in serovar Typhimurium acid tolerance important for virulence in mammals show attenuated virulence in C. elegans (16). Similarly, the PhoP/Q signal transduction system and several of the genes located in the pathogenicity island 1 are required for virulence in both mammals and C. elegans (2,10). The identification of virulence factors that are important in both mammals and C. elegans can conceivably be explained by conserved interactions with the innate immunity systems (28) and/or similarities in the actual growth environment (e.g., nutrient levels).…”

mentioning

confidence: 99%

Caenorhabditis elegans as a Model To Determine Fitness of Antibiotic-Resistant Salmonella enterica Serovar Typhimurium

Paulander

Pennhag

Andersson

et al. 2007

Antimicrob Agents Chemother

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We used the ability of Salmonella enterica serovar Typhimurium to colonize the gut of Caenorhabditis elegans to measure the fitness costs imposed by antibiotic resistance mutations. The fitness costs determined in the nematode were similar to those measured in mice, validating its use as a simple host model to evaluate bacterial fitness.The persistence of antibiotic-resistant bacteria largely depends on the effect of the resistance mechanism on fitness (reviewed in references 3 and 4). The cost caused by resistance mutations can be decreased by second-site mutations that restore fitness without a loss of resistance (3,17,18). This process has been observed in many cases both in vitro (13,17,19,22,25) and in clinical settings (6,8,20,26). These findings suggest that antibiotic resistance may persist in the population for a long time and that the determination of fitness parameters is of great importance for predicting the risk of resistance development.Fitness costs are usually determined by comparing the growth rates of resistant and susceptible bacteria (3). Although mouse models have been used for these purposes, simpler invertebrates such as Caenorhabditis elegans have recently become more attractive for assessing the in vivo biological costs of antibiotic resistance (23, 24). Many bacterial genes known to be required for mammalian pathogenesis are needed also in the nematode (1,9,11,15,16,27,28). Some bacterial pathogens, such as Salmonella enterica serovar Typhimurium are able to establish a persistent infection in the intestine of C. elegans, reducing the life span of the host. Several genes needed for virulence in mammals are also required for pathogenesis in C. elegans (2,10,16,28), implying that the invasion and proliferation of serovar Typhimurium in the host intestine depend on mechanisms common to the nematode and mammals. This makes C. elegans a relevant model for determining the infectivity and fitness of antibiotic-resistant bacteria during a host infection.Virulence assays were performed as previously described (2) using C. elegans SS104 [glp-4 (ts)] (5), a temperature-sensitive mutant that produces progeny at 15°C but not at 25°C. At least 50 synchronized worms in larval stage L4 were transferred on solid nematode growth medium (NGM) (12) seeded with 10 l of serovar Typhimurium mixed 1:100 with the nonpathogenic Escherichia coli strain OP50 and maintained at 25°C. Both bacterial species grow on NGM agar with no mutual inhibition. The number of viable worms was monitored every day, and the percentages of nematode survival calculated by the KaplanMeier method (14) were used for plotting the percent survival as a function of time. Survival kinetics were compared by using the nonparametric log-rank test and were considered statistically different when P was Ͻ0.05. We found that the time to death for 50% of the nematodes was 9 days when fed with E. coli OP50 and 7 days after ingestion of the virulent wild-type strain LT2 of serovar Typhimurium (Fig. 1). As previously shown, the glp-4 (ts) strain resp...

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“…The PhoP/PhoQ regulators promote remodeling of the bacterial envelope, including upregulation of enzymes that modify LPS charge (Ernst et al, 1999a;Ernst et al, 2001). Mutations in the phoPQ operon decrease S. enterica survival within macrophages and increase susceptibility to cationic AMPs and acid pH (Garcia Vescovi et al, 1994).…”

Section: Bacterial Gene Regulation and Amp Resistancementioning

confidence: 99%

Antimicrobial Peptide Resistance Mechanisms of Human Bacterial Pathogens

Nizet

2006

Current Issues in Molecular Biology

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The critical role played by antimicrobial peptides (AMPs) in mammalian innate immunity is increasingly recognized. Bacteria differ in their intrinsic susceptibility to AMPs, and the relative resistance of some important human pathogens to these defense molecules is now appreciated as an important virulence phenotype. Experimental analysis has identified diverse mechanisms of bacterial AMP resistance including altered cell surface charge, active efflux, production of proteases or trapping proteins, and modification of host cellular processes. The contribution of these resistance mechanisms to pathogenesis is confirmed through direct comparison of wild-type bacteria and AMP-sensitive mutants using in vivo infection models. Knowledge of the molecular basis of bacterial AMP resistance may provide new targets for antimicrobial therapy of human infectious diseases.

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outer membrane remodeling: role in resistance to host innate immunity

Cited by 217 publications

References 51 publications

HIV-1 Adapts to a Retrocyclin with Cationic Amino Acid Substitutions That Reduce Fusion Efficiency of gp41

HIV-1 Adapts to a Retrocyclin with Cationic Amino Acid Substitutions That Reduce Fusion Efficiency of gp41

Caenorhabditis elegans as a Model To Determine Fitness of Antibiotic-Resistant Salmonella enterica Serovar Typhimurium

Antimicrobial Peptide Resistance Mechanisms of Human Bacterial Pathogens

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