The relative contribution of causal factors in the transition from infection to clinical chlamydial disease

Bonnie L Quigley,Jon Hanger,Miranda E Vidgen,Peter Timms,Scott Carver

doi:10.1038/s41598-018-27253-z

Bonnie L Quigley, Jon Hanger + Show 3 more

Open Access

https://doi.org/10.1038/s41598-018-27253-z

Copy DOI

Abstract

Chlamydia is a major bacterial pathogen in humans and animals globally. Yet 80% of infections never progress to clinical disease. Decades of research have generated an interconnected network linking pathogen, host, and environmental factors to disease expression, but the relative importance of these and whether they account for disease progression remains unknown. To address this, we used structural equation modeling to evaluate putative factors likely to contribute to urogenital and ocular chlamydial disease in the koala (Phascolarctos cinereus). These factors include Chlamydia detection, load, and ompA genotype; urogenital and ocular microbiomes; host sex, age, weight, body condition; breading season, time of year; location; retrovirus co-infection; and major histocompatibility complex class II (MHCII) alleles. We show different microbiological processes underpin disease progression at urogenital and ocular sites. From each category of factors, urogenital disease was most strongly predicted by chlamydial PCR detection and load, koala body condition and environmental location. In contrast, ocular disease was most strongly predicted by phylum-level Chlamydiae microbiome proportions, sampling during breeding season and co-infection with koala retrovirus subtype B. Host MHCII alleles also contributed predictive power to both disease models. Our results also show considerable uncertainty remains, suggesting major causal mechanisms are yet to be discovered.

Highlights

Chlamydia is a major bacterial pathogen world-wide, affecting humans, wildlife and livestock[1,2,3]
Over the many years of Chlamydia research, with multiple hosts and species of Chlamydia pathogens, a disconnect between infection and disease has existed: infection with a chlamydial pathogen does not always lead to clinical disease and, during clinical disease, the instigating chlamydial pathogen cannot always be detected. This suggests that more than just the chlamydial pathogen is necessary to progress from infection to disease and that clinical signs and pathological changes can persist with undetectable levels of the chlamydial organism
Several microbiological, host and environmental factors have been implicated in contributing to clinical disease, but no attempt had yet been made to combine these factors into a predictive model of clinical chlamydial disease to aid in understanding their complex relationships

Summary

Introduction

Chlamydia is a major bacterial pathogen world-wide, affecting humans, wildlife and livestock[1,2,3]. Chlamydial disease has been extensively studied in both humans and koalas, with these hosts sharing a high degree of overlap in contributing factors to disease progression These bodies of research have revealed that humans and koalas share comparable urogenital and ocular disease presentations and outcomes[1,3]. A range of modelling studies have investigated chlamydial infection leading to disease ( focused on pelvic inflammatory disease23), but none has investigated the range of contributing factors in a unified analysis To close this gap, we developed structural equation models (SEMs) for urogenital and ocular chlamydial clinical disease, using the koala as a model system. SEMs can be a valuable tool to understanding how multiple factors come together in a disease setting Using this approach, we determined that different contributing factors lead to clinical urogenital and ocular chlamydial disease. We show that considerable unexplained variation remains and, more factors may need to be considered in order to understand the progression of chlamydial infection to clinical disease

Methods

Results

Conclusion