Love Me Love My Phages

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  Love Me Love My Phages

http://www.icddrb.org/pub/publication.jsp?classificationID=46&pubID=7544

 Cholera epidemics and the role bacteriophages may play in ending them

 Cholera epidemics (caused by the bacterium Vibrio cholerae) cause widespread illness and death in developing countries. The Ganges Delta region of Bangladesh and India, for example, suffers two cholera epidemics each year. ICDDR,B researchers and Harvard Medical School have therefore been working to identify what factors trigger and end these seasonal epidemics. Results suggest that bacteriophages (viruses that attack bacteria) may play a key role.

"Researchers will use their
improved understanding of
the interactions among hosts,
V. cholerae, and cholera-killing
bacteriophages to identify
new ways of preventing
cholera epidemics"

 During a three-year study of patients in ICDDR,B’s Dhaka hospital, researchers confirmed that the number of cholera patients (which varied seasonally) often coincided with the presence of disease-causing V. cholerae strains in water samples. They also showed that, during epidemic-free periods, water supplies typically contained cholera-killing phages but no viable bacteria.

 

Importantly, researchers also found that the phage peak in water samples coincided with a rise in the number of phages found in the excrement of cholera patients. So, it seems that the epidemics are ended by phages which amplify in people with cholera—these then attack the cholera bacteria once they are excreted and enter water supplies. This may well explain why the seasonal cholera epidemics that occur in Bangladesh are self-limiting.

Before the development of modern antimicrobials, phage therapy was considered a feasible option for the treatment of bacterial infection. The study team will therefore use their improved understanding of the interactions among hosts, V. cholerae,and cholera phages to identify new ways of preventing cholera epidemics

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Phage in the Time of Cholera

Joshua S. Weitz

1*

, and Hyman Hartman

2

1

Department of Ecology and Evolutionary Biology,

Princeton University, Princeton, NJ 08544.

Email: jsweitz@princeton.edu

*

Corresponding author

2

Center for Biomedical Engineering,

Massachusetts Institute of Technology, Cambridge, MA 02139.

Email: hhartman@mit.edu

January 27, 2006

Bacteriophage (bacterial viruses) were heralded as revolutionary therapeutic agents

soon after the discovery by Félix d’Herelle in 1917 of an “invisible microbe”

capable of lysing bacteria

1

. Bacteriophage appeared to be efficient killers of their

bacterial hosts – we now know that their life history is far more complex than first

assumed

2

– and so the effort to use phage as curatives or prophylaxis spread

quickly to research institutes in Europe, North America, and Asia

3

. d’Herelle

himself spearheaded many of these efforts, the most famous of which was the

initiation of an extensive campaign to use phage in the treatment and prevention of

cholera in colonial India. The authors of one such study conclude by noting that

“the results establish sufficient probability in favour of a significant effect of the

administration of bacteriophage to form a basis of practical policy in the treatment

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and prevention of cholera in villages”

4

. The early hopes never fulfilled

expectations, for both clinical and political reasons

3

, and the eventual development

of broad spectrum antibiotics provided a more reliable, effective means of

controlling bacterial infections. The rise of antibiotic resistance has, in turn,

revived interest in bacteriophage therapy despite concerns and uncertainties as to

its effectiveness

5

. We consider here an alternative approach to modern

bacteriophage therapy, by revisiting the idea of inoculating bacteriophage directly

into the environment.

Most tests, theories, and proposals to implement bacteriophage therapy

regard the human body as the potential site for intervention

6,7

. But for many

bacterial diseases affecting human health, the pool of infecting bacteria comes

from water, soils, food, and other host organisms; some of these potential sources

of infection do not possess a complex immune system capable of selectively

eliminating foreign agents. In contrast to agricultural settings where environmental

application of phage as biocontrol is already being considered

8

, we believe there

exists an as yet overlooked opportunity to reduce the severity, extent, and

persistence of some bacterial epidemics by developing ecological-based cures for

human disease.

A suitable target disease is cholera. Recent studies have demonstrated a

significant correlation between the increase in density of cholera-specific phage

and the decrease in density of Vibrio cholerae (in both water sources and fecal

matter from infected patients)

9,10

. The reasons are apparently simple: presence of

V. cholerae provides an opportunity for the spread and increase of phage which

leads to decreasing host density, which in turns leads to the washout/death of

phage. A comprehensive description of cholera disease dynamics involves many

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factors including environmental seasonality

11

, long-distance dispersal mediated by

alternative hosts

12

, as well as life-history modalities that enable V. cholerae to

respond to stressful conditions

13

. Without diminishing the importance of these and

other factors, in the case of cholera it is apparent that phage and bacteria go

through alternating boom-and-bust cycles. What are the practical steps of

intervention so as to minimize the likelihood of devastating epidemic booms of V.

cholerae?

Briefly, the peak of phage lags behind the peak of bacteria. Growing up O1

and/or O139 serogroup-specific phage in the lab, therapy by the flask as it were,

and then adding phage to at-risk water sources may augment the ability of phage to

keep pace with the dynamics of its host and suppress the spread of an epidemic. In

a sense, we are suggesting altering the “natural course”

10

of host-phage population

dynamics with an artificial injection of phage. The utility and effectiveness of any

such ecological inoculation depend on careful balancing of environmental

connectivity of infected areas, risks to human populations, as well as the life-

history and parameterization of the biocontrol agent themselves. Ultimately,

limiting and/or eliminating an undesirable bacterial population constitutes a

problem in coevolutionary biological control. Recent theoretical work on

coevolutionary dynamics of bacteria and bacteriophage in simple aquatic

environments demonstrates that coevolution-induced outcomes, e.g. eradication of

phage and host, sequential strain replacement, or host-phage diversification,

depend on characterizing (and possibly manipulating) rates of mutagenesis, host

growth rate and strain-specific adsorption rates, and host-range characteristics of

mutants

14

. However, the ecology of natural environments is far more complex.

Likely sites for intervention include sources of drinking water, wells, and sewage

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systems so as to minimize the flow of bacterial agents into water used for drinking

and bathing. Assessments of the lifetime of phage in local habitats would be

necessary as conditions (e.g., temperature, salinity, pH) change over the course of

intervention. In addition, the ecohydrology of the affected region may be

important, as intervention strategies will depend on whether disease outbreaks are

localized to isolated sites, linked to seasonal flooding, or occur along riverine

corridors.

These concerns notwithstanding, cholera-specific phage are already found

in natural environments and there exists strong evidence to suggest that their

presence leads to the decline of cholera epidemics

10

. The risks associated with

ecological bacteriophage therapy should be mitigated by the use of virulent, in

contrast to temperate, strains of phage. In this regard, the previously identified lytic

phages JSF1 and/or JSF5 specific to V. cholerae serogroup O1 seem ideal

candidates for initial studies

10

. If the origins of seasonal cholera epidemics are

harbored within environmental pools, then efforts should be made to seek out the

most effective means of adding bacteriophage to eliminate the incubation and

growth of V. cholerae populations when they are at their most vulnerable.

Diminishing the density of V. cholerae would also be important to impeding the

spread of disease, since the infectious dose is generally considered to be on the

order of 10

4

bacterial cells. Thus far, the spread of cholera has been mitigated by

improvements in water quality, low-cost preventative measures in at-risk regions,

e.g., filtering water through sari cloth

15

, as well as by improvements in post-

infection treatment, e.g., single-dose antibiotic therapy

16

, though the global cholera

pandemic has not abated. Bacteriophage could become an additional tool in the

public health struggle against cholera. The initiation of controlled experiments that

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incorporate recent advances in the genetics and evolutionary ecology of phage may

offer hope that d’Herelle’s early mission to eradicate cholera in the Indian

subcontinent need not have been in vain.

References

[1] d’Herelle, F. Sur un microbe invisible antagoniste des bacilles dysentèriques.

Cr. R. Acad. Sci. Paris 165 (1917).

[2] Weinbauer, M. Ecology of prokaryotic viruses. FEMS Microbiology Reviews

28, 127–81 (2004).

[3] Summers, W. Félix d’Herelle and the Origins of Molecular Biology (Yale

University Press, 1999).

[4] Morison, J., Rice, E. & Pal Choudhury, B. Bacteriophage in the treatment and

prevention of cholera. Indian Journal of Medical Research 21, 790–907 (1934).

[5] Thiel, K. Old dogma, new tricks – 21st Century phage therapy. Nature

Biotechnology 22, 31–6 (2004).

[6] Merril, C., Scholl, D. & Adhya, S. The prospect for bacteriophage therapy in

Western medicine. Nature Reviews Drug Discovery 6, 489– 97 (2003).

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Nature Reviews Microbiology 2, 166–73 (2004).

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[9] Faruque, S. et al. Seasonal epidemics of cholera inversely correlate with the

prevalence of environmental cholera phages. Proceedings of the National Academy

of Sciences, USA 102, 1702–7 (2005).

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[10] Faruque, S. et al. Self-limiting nature of aseasonal cholera epidemics: Role of

host-mediated amplification of phage. Proceedings of the National Academy of

Sciences, USA 102, 6119–24 (2005).

[11] Koelle, K., Rodó, Pascual, M., Yunus, M. & Mostafa, G. Refractory periods

and climate forcing in cholera dynamics. Nature 436, 696–700 (2005).

[12] Colwell, R. Global climate and infectious disease: the cholera paradigm.

Science 274, 2025–31 (1996).

[13] Roszak, D. & Colwell, R. Survival strategies of bacteria in the natural

environment. Microbiology Reviews 51, 365–79 (1987).

[14] Weitz, J., Hartman, H. & Levin, S. Coevolutionary arms races between

bacteria and bacteriophage. Proceedings of the National Academy of Sciences,

USA 102, 9535–40 (2005).

[15] Colwell, R. et al. Reduction of cholera in Bangladeshi villages by simple

filtration. Proceedings of the National Academy of Sciences, USA 100, 1051–1055

(2003).

[16] Saha, D. et al. Single-dose ciproflaxacin versus 12-dose erythromycin for

childhood cholera: a randomised controlled trial. The Lancet DOI:10.1016/S0140–

6736(05)67290–X (2005).

 

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 Love Me Love My Phages