Glucose levels affect LL-37 expression in monocyte-derived macrophages altering the Mycobacterium tuberculosis intracellular growth control

Montoya-Rosales, Alejandra; Castro-Garcia, Pamela; Torres-Juárez, Flor; Enciso-Moreno, José Antonio; Rivas-Santiago, Bruno

doi:10.1016/j.micpath.2016.06.002

Cited by 27 publications

(28 citation statements)

References 28 publications

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“…From these data, we cannot differentiate the source of cathelicidin in STZ-treated mice since bladder epithelial cells, as well as mast cells, neutrophils, and other myeloid lineage cells (which were increased in STZ-treated mice), are all known to produce cathelicidin. Higher cathelicidin in diabetes has been identified at inflamed mucosal cites (55), in the kidneys during acidosis (107), and in infected macrophages (108). Additionally, GBS burdens were no different between diabetic and nondiabetic Camp Ϫ/Ϫ mice in our model (Fig.…”

Section: Discussionsupporting

confidence: 49%

Host Cathelicidin Exacerbates Group BStreptococcusUrinary Tract Infection

Patras

Coady

Babu

et al. 2020

mSphere

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Group B Streptococcus (GBS) causes frequent urinary tract infection (UTI) in susceptible populations, including individuals with type 2 diabetes and pregnant women; however, specific host factors responsible for increased GBS susceptibility in these populations are not well characterized. Here, we investigate cathelicidin, a cationic antimicrobial peptide, known to be critical for defense during UTI with uropathogenic Escherichia coli (UPEC). We observed a loss of antimicrobial activity of human and mouse cathelicidins against GBS and UPEC in synthetic urine and no evidence for increased cathelicidin resistance in GBS urinary isolates. Furthermore, we found that GBS degrades cathelicidin in a protease-dependent manner. Surprisingly, in a UTI model, cathelicidin-deficient (Camp−/−) mice showed decreased GBS burdens and mast cell recruitment in the bladder compared to levels in wild-type (WT) mice. Pharmacologic inhibition of mast cells reduced GBS burdens and histamine release in WT but not Camp−/− mice. Streptozotocin-induced diabetic mice had increased bladder cathelicidin production and mast cell recruitment at 24 h postinfection with GBS compared to levels in nondiabetic controls. We propose that cathelicidin is an important immune regulator but ineffective antimicrobial peptide against GBS in urine. Combined, our findings may in part explain the increased frequency of GBS UTI in diabetic and pregnant individuals. IMPORTANCE Certain populations such as diabetic individuals are at increased risk for developing urinary tract infections (UTI), although the underlying reasons for this susceptibility are not fully known. Additionally, diabetics are more likely to become infected with certain types of bacteria, such as group B Streptococcus (GBS). In this study, we find that an antimicrobial peptide called cathelicidin, which is thought to protect the bladder from infection, is ineffective in controlling GBS and alters the type of immune cells that migrate to the bladder during infection. Using a mouse model of diabetes, we observe that diabetic mice are more susceptible to GBS infection even though they also have more infiltrating immune cells and increased production of cathelicidin. Taken together, our findings identify this antimicrobial peptide as a potential contributor to increased susceptibility of diabetic individuals to GBS UTI.

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Section: Discussionsupporting

confidence: 49%

Host Cathelicidin Exacerbates Group BStreptococcusUrinary Tract Infection

Patras

Coady

Babu

et al. 2020

mSphere

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“…Mtb being an extremely successful intracellular pathogen, can remain within the host system by keeping the immune responses under control via a wide repertoire of escape pathways ( 8 ). To complicate matters further, latent tubercle bacilli infections have become a serious global threat because of the challenge in diagnosing them clinically and their regular conversion from dormancy to active infections in immunocompromised circumstances, due to HIV coinfection, immunosuppressive therapies ( 9 , 10 ) or diabetes mellitus type 2 conditions ( 11 ). Although novel drug susceptibility testing methodologies, such as the GeneXpert ® MTB/RIF ( 12 , 13 ) and HT-SPOTi ( 14 ), are enabling the early detection of antibiotic-resistant strains, a complete comprehension of the host immune capability and the mode by which Mtb handles/endures/evades the host defenses will be needed to eradicate this infectious disease ( 15 ).…”

Section: Introductionmentioning

confidence: 99%

Host Antimicrobial Peptides: The Promise of New Treatment Strategies against Tuberculosis

Arranz-Trullén

Pulido

et al. 2017

Front. Immunol.

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Tuberculosis (TB) continues to be a devastating infectious disease and remerges as a global health emergency due to an alarming rise of antimicrobial resistance to its treatment. Despite of the serious effort that has been applied to develop effective antitubercular chemotherapies, the potential of antimicrobial peptides (AMPs) remains underexploited. A large amount of literature is now accessible on the AMP mechanisms of action against a diversity of pathogens; nevertheless, research on their activity on mycobacteria is still scarce. In particular, there is an urgent need to integrate all available interdisciplinary strategies to eradicate extensively drug-resistant Mycobacterium tuberculosis strains. In this context, we should not underestimate our endogenous antimicrobial proteins and peptides as ancient players of the human host defense system. We are confident that novel antibiotics based on human AMPs displaying a rapid and multifaceted mechanism, with reduced toxicity, should significantly contribute to reverse the tide of antimycobacterial drug resistance. In this review, we have provided an up to date perspective of the current research on AMPs to be applied in the fight against TB. A better understanding on the mechanisms of action of human endogenous peptides should ensure the basis for the best guided design of novel antitubercular chemotherapeutics.

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“…These findings point to the added need to Tables 2 and 3. investigate TB-DM patients with extra-pulmonary and/or negative AFB smears to identify any other underlying immunological change that can synergize to increase their risk of death. Further stratification of TB-DM patients with clinical history and laboratory findings such as diabetes history or glucose control are likely to refine the predictions further, as suggested previously [16,19,32,33] and further refinement could be achieved by additional measures of immune status, which are under development in research laboratories.…”

Section: Discussionmentioning

confidence: 88%

“…HLA-DRB1*14 allele) have been documented in other studies, but such variables were not available in our dataset [30,31]. Good DM control also would likely be important in explaining the residual variation among the DM patients [16,19,32], given that higher glucose levels were previously shown to affect innate immunity and change specific peptide expression in TB-infected cells leading to a higher bacterial load; but glucose levels were not available in our dataset [33]. Given that drug testing policies differ between the border and non-border sanitary jurisdictions based on available resources, we tried to develop a model using only the data from the border jurisdictions where drug testing is more comprehensive to help improve predictability, but the model yielded a very low c-statistic (c-statistic = 0•52; not shown).…”

Section: Discussionmentioning

confidence: 99%

Predicting treatment failure, death and drug resistance using a computed risk score among newly diagnosed TB patients in Tamaulipas, Mexico

Abdelbary¹,

García

Ramirez-Oropesa

et al. 2017

Epidemiol. Infect.

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The purpose of this study was to develop a method for identifying newly diagnosed tuberculosis (TB) patients at risk for TB adverse events in Tamaulipas, Mexico. Surveillance data between 2006 and 2013 (8431 subjects) was used to develop risk scores based on predictive modelling. The final models revealed that TB patients failing their treatment regimen were more likely to have at most a primary school education, multi-drug resistance (MDR)-TB, and few to moderate bacilli on acid-fast bacilli smear. TB patients who died were more likely to be older males with MDR-TB, HIV, malnutrition, and reporting excessive alcohol use. Modified risk scores were developed with strong predictability for treatment failure and death (c-statistic 0·65 and 0·70, respectively), and moderate predictability for drug resistance (c-statistic 0·57). Among TB patients with diabetes, risk scores showed moderate predictability for death (c-statistic 0·68). Our findings suggest that in the clinical setting, the use of our risk scores for TB treatment failure or death will help identify these individuals for tailored management to prevent these adverse events. In contrast, the available variables in the TB surveillance dataset are not robust predictors of drug resistance, indicating the need for prompt testing at time of diagnosis.

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Glucose levels affect LL-37 expression in monocyte-derived macrophages altering the Mycobacterium tuberculosis intracellular growth control

Cited by 27 publications

References 28 publications

Host Cathelicidin Exacerbates Group BStreptococcusUrinary Tract Infection

Host Cathelicidin Exacerbates Group BStreptococcusUrinary Tract Infection

Host Antimicrobial Peptides: The Promise of New Treatment Strategies against Tuberculosis

Predicting treatment failure, death and drug resistance using a computed risk score among newly diagnosed TB patients in Tamaulipas, Mexico

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