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      Transmission of Vibrio cholerae Is Antagonized by Lytic Phage and Entry into the Aquatic Environment

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          Cholera outbreaks are proposed to propagate in explosive cycles powered by hyperinfectious Vibrio cholerae and quenched by lytic vibriophage. However, studies to elucidate how these factors affect transmission are lacking because the field experiments are almost intractable. One reason for this is that V. cholerae loses the ability to culture upon transfer to pond water. This phenotype is called the active but non-culturable state (ABNC; an alternative term is viable but non-culturable) because these cells maintain the capacity for metabolic activity. ABNC bacteria may serve as the environmental reservoir for outbreaks but rigorous animal studies to test this hypothesis have not been conducted. In this project, we wanted to determine the relevance of ABNC cells to transmission as well as the impact lytic phage have on V. cholerae as the bacteria enter the ABNC state. Rice-water stool that naturally harbored lytic phage or in vitro derived V. cholerae were incubated in a pond microcosm, and the culturability, infectious dose, and transcriptome were assayed over 24 h. The data show that the major contributors to infection are culturable V. cholerae and not ABNC cells. Phage did not affect colonization immediately after shedding from the patients because the phage titer was too low. However, V. cholerae failed to colonize the small intestine after 24 h of incubation in pond water—the point when the phage and ABNC cell titers were highest. The transcriptional analysis traced the transformation into the non-infectious ABNC state and supports models for the adaptation to nutrient poor aquatic environments. Phage had an undetectable impact on this adaptation. Taken together, the rise of ABNC cells and lytic phage blocked transmission. Thus, there is a fitness advantage if V. cholerae can make a rapid transfer to the next host before these negative selective pressures compound in the aquatic environment.

          Author Summary

          The biological factors that control the transmission of water-borne pathogens like Vibrio cholerae during outbreaks are ill defined. In this study, a molecular analysis of the active but non-culturable (ABNC) state of V. cholerae provides insights into the physiology of environmental adaptation. The ABNC state, lytic phage, and hyperinfectivity were concurrently followed as V. cholerae passaged from cholera patients to an aquatic reservoir. The relevance to transmission of each factor was weighed against the others. As the bacteria transitioned from the patient to pond water, there was a rapid decay into the ABNC state and a rise of lytic phage that compounded to block transmission in a mouse model. These two factors give reason for V. cholerae to make a quick transit through the environment and onto the next human host. Thus, in over-crowded locations with failed water infrastructure, the opportunity for fast transmission coupled with the increased infectivity and culturability of recently shed V. cholerae creates a charged setting for explosive cholera outbreaks.

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          Child survival efforts can be effective only if they are based on accurate information about causes of deaths. Here, we report on a 4-year effort by WHO to improve the accuracy of this information. WHO established the external Child Health Epidemiology Reference Group (CHERG) in 2001 to develop estimates of the proportion of deaths in children younger than age 5 years attributable to pneumonia, diarrhoea, malaria, measles, and the major causes of death in the first 28 days of life. Various methods, including single-cause and multi-cause proportionate mortality models, were used. The role of undernutrition as an underlying cause of death was estimated in collaboration with CHERG. In 2000-03, six causes accounted for 73% of the 10.6 million yearly deaths in children younger than age 5 years: pneumonia (19%), diarrhoea (18%), malaria (8%), neonatal pneumonia or sepsis (10%), preterm delivery (10%), and asphyxia at birth (8%). The four communicable disease categories account for more than half (54%) of all child deaths. The greatest communicable disease killers are similar in all WHO regions with the exception of malaria; 94% of global deaths attributable to this disease occur in the Africa region. Undernutrition is an underlying cause of 53% of all deaths in children younger than age 5 years. Achievement of the millennium development goal of reducing child mortality by two-thirds from the 1990 rate will depend on renewed efforts to prevent and control pneumonia, diarrhoea, and undernutrition in all WHO regions, and malaria in the Africa region. In all regions, deaths in the neonatal period, primarily due to preterm delivery, sepsis or pneumonia, and birth asphyxia should also be addressed. These estimates of the causes of child deaths should be used to guide public-health policies and programmes.
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                Author and article information

                Role: Editor
                PLoS Pathog
                PLoS Pathogens
                Public Library of Science (San Francisco, USA )
                October 2008
                October 2008
                24 October 2008
                : 4
                : 10
                [1 ]Howard Hughes Medical Institute and the Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, Massachusetts, United States of America
                [2 ]Microbiology Department, Jahangirnagar University, Savar, Dhaka, Bangladesh
                [3 ]Tufts Expression Array Core (TEAC) Facility, Tufts University School of Medicine, Boston, Massachusetts, United States of America
                [4 ]Institut fuer Molekulare Biowissenschaften, Karl-Franzens-Universitaet Graz, Graz, Austria
                [5 ]Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, United States of America, and Harvard Medical School, Boston, Massachusetts, United States of America
                [6 ]International Centre for Diarrhoeal Disease Research, Dhaka, Bangladesh
                Massachusetts General Hospital, United States of America
                Author notes

                Conceived and designed the experiments: E. Nelson, J. Flynn, S. Schild, L. Bourassa, R. LaRocque, S. Calderwood, F. Qadri, A. Camilli. Performed the experiments: E. Nelson, A. Chowdhury, S. Schild, L. Bourassa, Y. Shao. Analyzed the data: E. Nelson, J. Flynn, A. Camilli. Contributed reagents/materials/analysis tools: E. Nelson, J. Flynn, R. LaRocque, S. Calderwood, F. Qadri, A. Camilli. Wrote the paper: E. Nelson, A. Camilli.

                Nelson et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                Page count
                Pages: 15
                Research Article
                Infectious Diseases
                Infectious Diseases/Bacterial Infections
                Infectious Diseases/Epidemiology and Control of Infectious Diseases
                Infectious Diseases/Gastrointestinal Infections
                Infectious Diseases/Neglected Tropical Diseases
                Infectious Diseases/Tropical and Travel-Associated Diseases
                Microbiology/Applied Microbiology
                Microbiology/Cellular Microbiology and Pathogenesis
                Microbiology/Environmental Microbiology
                Microbiology/Medical Microbiology
                Microbiology/Microbial Physiology and Metabolism
                Molecular Biology
                Molecular Biology/Bioinformatics
                Public Health and Epidemiology

                Infectious disease & Microbiology


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