Rebecca L. Laws

Identification of innate immunity genes and pathways using a comparative genomics approach

To reveal regulators of innate immunity, we used RNAi assays to monitor the immune response when genes are inhibited in Caenorhabditis elegans and mouse macrophages. Genes that altered innate immune responsiveness in C. elegans were validated in murine macrophages, resulting in the discovery of 11 genes that regulate the innate immune response in both systems and the subsequent identification of a protein interaction network with a conserved role in innate immunity regulation. We confirmed the role of four of these 11 genes in antimicrobial gene regulation using available mutants in C. elegans. Several of these genes (acy-1, tub-2, and tbc-1) also regulate susceptibility to the pathogen Pseudomonas aeruginosa. These genes may prove critical to understanding host defense and represent potential therapeutic targets for infectious and immunological diseases.

Changes in kidney function among Nicaraguan sugarcane workers

Abstract Background: There is an epidemic of chronic kidney disease (CKD) of unknown etiology in Central American workers. Objectives: To investigate changes and job-specific differences in kidney function over a 6-month sugarcane harvest season, explore the potential role of hydration, and measure proteinuria. Methods: We recruited 284 Nicaraguan sugarcane workers performing seven distinct tasks. We measured urine albumin and serum creatinine and estimated glomerular filtration rate (eGFR). Results: eGFR varied by job and decreased during the harvest in seed cutters (−8·6 ml/min/1·73 m2), irrigators (−7·4 ml/min/1·73 m2), and cane cutters (−5·0 ml/min/1·73 m2), as compared to factory workers. The number of years employed at the company was negatively associated with eGFR. Fewer than 5% of workers had albumin-to-creatinine ratio (ACR) >30 mg/g. Conclusions: The decline in kidney function during the harvest and the differences by job category and employment duration provide evidence that one or more risk factors of CKD are occupational.

Urine biomarkers of kidney injury among adolescents in Nicaragua, a region affected by an epidemic of chronic kidney disease of unknown aetiology

BACKGROUND An epidemic of chronic kidney disease (CKD) of non-traditional aetiology has been recently recognized by health authorities as a public health priority in Central America. Previous studies have identified strenuous manual work, agricultural activities and residence at low altitude as potential risk factors; however, the aetiology remains unknown. Because individuals are frequently diagnosed with CKD in early adulthood, we measured biomarkers of kidney injury among adolescents in different regions of Nicaragua to assess whether kidney damage might be initiated during childhood. METHODS Participants include 200 adolescents aged 12-18 years with no prior work history from four different schools in Nicaragua. The location of the school served as a proxy for environmental exposures and geographic locations were selected to represent a range of factors that have been associated with CKD in adults (e.g. altitude, primary industry and CKD mortality rates). Questionnaires, urine dipsticks and kidney injury biomarkers [interleukin-18, N-acetyl-d-glucosaminidase (NAG), neutrophil gelatinase-associated lipocalin (NGAL) and albumin-creatinine ratio] were assessed. Biomarker concentrations were compared by school using linear regression models. RESULTS Protein (3.5%) and glucose (1%) in urine measured by dipstick were rare and did not differ by school. Urine biomarkers of tubular kidney damage, particularly NGAL and NAG, showed higher concentrations in those schools and regions within Nicaragua that were defined a priori as having increased CKD risk. Painful urination was a frequent self-reported symptom. CONCLUSIONS Although interpretation of these urine biomarkers is limited because of the lack of population reference values, results suggest the possibility of early kidney damage prior to occupational exposures in these adolescents.

Comparative Genomics RNAi Screen Identifies Eftud2 as a Novel Regulator of Innate Immunity

The extent of the innate immune response is regulated by many positively and negatively acting signaling proteins. This allows for proper activation of innate immunity to fight infection while ensuring that the response is limited to prevent unwanted complications. Thus mutations in innate immune regulators can lead to immune dysfunction or to inflammatory diseases such as arthritis or atherosclerosis. To identify novel innate immune regulators that could affect infectious or inflammatory disease, we have taken a comparative genomics RNAi screening approach in which we inhibit orthologous genes in the nematode Caenorhabditis elegans and murine macrophages, expecting that genes with evolutionarily conserved function also will regulate innate immunity in humans. Here we report the results of an RNAi screen of approximately half of the C. elegans genome, which led to the identification of many candidate genes that regulate innate immunity in C. elegans and mouse macrophages. One of these novel conserved regulators of innate immunity is the mRNA splicing regulator Eftud2, which we show controls the alternate splicing of the MyD88 innate immunity signaling adaptor to modulate the extent of the innate immune response.

Leptospira seropositivity as a risk factor for Mesoamerican Nephropathy

Abstract Background: Leptospirosis is postulated as a possible cause of Mesoamerican Nephropathy (MeN) in Central American workers. Objectives: Investigate job-specific Leptospira seroprevalence and its association with kidney disease biomarkers. Methods: In 282 sugarcane workers, 47 sugarcane applicants and 160 workers in other industries, we measured anti-leptospiral antibodies, serum creatinine, and urinary injury biomarkers, including neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18), and N-acetyl-D-glucosaminidase (NAG). Results: Leptospira seroprevalence differed among job categories and was highest among sugarcane cutters (59%). Seropositive sugarcane workers had higher NGAL concentrations (relative mean: 1.28; 95% CI: 0.94–1.75) compared to those who were seronegative, with similar findings among field and non-field workers. Conclusions: Leptospira seroprevalence varied by job category. There was some indication that seropositivity was associated with elevated biomarker levels, but results were inconsistent. Additional studies may help establish whether Leptospira infection plays any role in MeN among Central American workers.