Manual Control of Human Parasitic Diseases (Advances in Parasitology)

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The concepts of eradication, elimination and control are defined and examples of success summarized. Overviews of the health policy and financing environment in which programmes to control or eliminate parasitic diseases are positioned and the development of public-private partnerships as vehicles for product development or access to drugs for parasite disease control are discussed. It is also widely accepted that the level of investment in drug development for the parasitic diseases of poor populations is an unattractive option for pharmaceutical companies.

The development of partnerships to specifically address this need provides some hope that the intractable problems of the treatment regimens for the trypanosomiases and leishmaniases can be solved in the not too distant future. However, it will be difficult to implement and sustain such interventions in fragile health services often in settings where resources are limited but also in unstable, conflict-affected or post-conflict countries. Emphasis is placed on the importance of co-endemicity and polyparasitism and the opportunity to control parasites susceptible to cost-effective and proven chemotherapeutic interventions for a package of diseases which can be implemented at low cost and which would benefit the poorest and most marginalized groups.

The ecology of parasitic diseases is discussed in the context of changing ecology, environment, sociopolitical developments and climate change.

These drivers of global change will affect the epidemiology of parasites over the coming decades, while in many of the most endemic and impoverished countries parasitic infections will be accorded lower priority as resourced stressed health systems cope with the burden of the higher-profile killing diseases viz. There is a need for more holistic thinking about the interactions between parasites and other infections.

It is clear that as the prevalence and awareness of HIV has increased, there is a growing recognition of a host of complex interactions that determine disease outcome in individual patients. The competition for resources in the health as well as other social sectors will be a continuing challenge; effective parasite control will be dependent on how such resources are accessed and deployed to effectively address well-defined problems some of which are readily amenable to successful interventions with proven methods.

The opportunities and challenges for the study and control of parasitic diseases in the 21st century are both exciting and daunting. Based on the contributions from this field over the last part of the 20th century, we should expect new biologic concepts will continue to come from this discipline to enrich the general area of biomedical research.

Such characteristics force biological systems to their limits, and this may be why studies of these diseases have made fundamental contributions to molecular biology, cell biology and immunology. However, if these findings are to continue apace, parasitologists must capitalize on the new findings being generated though genomics, bioinformatics, proteomics, and genetic manipulations of both host and parasite. Furthermore, they must do so based on sound biological insights and the use of hypothesis-driven studies of these complex systems. A major challenge over the next century will be to capitalize on these new findings and translate them into successful, sustainable strategies for control, elimination and eradication of the parasitic diseases that pose major public health threats to the physical and cognitive development and health of so many people worldwide.

Human parasitic diseases are caused by numerous, widely disparate infectious organisms. Many require transmission by complex vectors. Some involve intermediate hosts. A few can be acutely lethal. Many result in chronic infections that often cause severe morbidity in only a relatively small proportion of those infected.

Several are among the most prevalent infections in the world, and severe morbidity in even a low percentage of those infected results in major global burdens of disease. Some occur only sporadically and infrequently. These seemingly all-encompassing characteristics make parasitic diseases some of the most interesting, challenging and important infectious diseases facing scientists, clinicians, and public health officials as we move into the 21st century.

Control of human parasitic diseases: Context and overview.

This presentation will address the future of parasitology by first citing examples of the recent progress and contributions from this field, and then by examining some of the scientific and public health promises and challenges that lie before us. The role of basic biomedical research is to discover and understand the fundamental processes of how cells and organisms work.

I believe that parasites and parasitic diseases are good systems for fundamental investigations because of their inherent complexity and their apparent necessity to develop unique "outer limit" mechanisms to solve their survival needs. The down-side of this, of course, is also their complexity. Sorting out how these things happen is challenging, but the observations are often there. The burden is then on the investigator to determine how to attack the problem with productive experimental approaches and how to grasp the appropriate understanding of what is observed.

In the world of molecular biology this approach has been best seen in the early and continuing work on African trypanosomes, where the molecular mechanisms that provide the basis of antigenic variation Borst et al. These organisms, which must survive in the hostile environment of the host's blood, totally exposed to the host's immune mechanisms, exhibit fundamental mechanisms that suit their needs Donelson et al. The additional finding and mechanistic understanding of RNA processing by trans-splicing in nematodes Nilsen and other organisms further illustrates the means used by such eucaryotes to accomplish their needs, expanding how we think about molecular machinery and options.

Cell biologists interested in parasites are continually learning that various organisms contain previously unrecognized organelles to allow them to perform in their particular host environments, and that these organelles often accomplish tasks in previously unknown ways. It is now clear that almost all apicomplexans including Plasmodium, Toxoplasma, Babesia, and Eimeria contain an endosymbiotic organelle called an "apicoplast" Roos et al.

The fact that the apicoplast is essential to these organisms is now clear, as is its algal origin, the sequence of its 35kB genome, and its existence within a 4 unit membrane.

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However, its actual essential function is still unclear Roos et al. The apparent lack of an apicoplast in the apicomplexan Cryptosporidium parvum Zhu et al. Trichomonads contain a unique organelle called the hydro-genosome, which lacks DNA, cytochromes, or the citric acid cycle, but rather produces ATP using pyruvate as a primary substrate, in conjunction with enzymes typical of anaerobic bacteria Muller , Johnson et al.

It is called an acidocalcisome. Trypanosoma cruzi at first actually penetrates its host cells in part using cell lysosomal fusion Tardieux et al.

Several protozoan parasites, including Plasmodium spp. In a truly outstanding feat, the nematode Trichinella spiralis is also an intracellular pathogen.

Parasitic Diseases Lectures #4: Giardiasis

This worm actually enters a striated skeletal muscle cell, which serve as its host cell in its tissue phase, and commandeers the cell machinery to an extent that the cell becomes what is known as a "nurse cell" Despommier Nurse cells develop and maintain T. Immunoparasitology has provided important insights into fundamental cellular and humoral immune mechanisms that contribute to all of immunology.

A wide variety of immune evasion mechanisms are used by various parasites. Perhaps the best known has already been mentioned, the antigenic variation expressed by African trypanosomes Borst et al. However, there are many other clever strategies used by parasites. Tissue-dwelling cestodes display a co-existence trick that involves the control of host complement activation.

The hydatid cysts of Echinococcus granulosus and Taenia solium in its cysticercosis metacestode form are very effective at actively avoiding complement activation via, among other mechanisms, sequestration of factor H and elaboration of paramyosin, which inhibits C1q White et al.

It is clear that various intracellular protozoans distinctly alter the capabilities of host macrophages Reiner , LaFlamme et al.

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This frontal assault on the fundamental immune presentation mechanisms of the host can considerably alter how immune responses are mounted. Once more fully understood, this knowledge might be useful in directing altered immune capabilities. Through the elaboration of these findings, and the reverse side of the story involving differential Th2 stimulation by various helminths such as schistosomes and filarids Scott et al. These insights will prove valuable in trying to further understand various autoimmune diseases, asthma and atopic allergies, and various immune diseases involving granuloma formation and its regulation.

Coupled with the discussion of potential unique drug targets in protozoan organelles described above, it also bears mentioning that work on parasite cysteine proteases and their inhibitors is a major contributor to the very active field of protease inhibitors as effective antimicrobial and antitumor agents McKerrow et al. Using inhibitor design models that are based on the structure of parasite cysteine proteases, it has been feasible to develop interesting leads for drugs against a spectrum of protozoans, including T. Examples of non-parasite targets of protease inhibitors include angiotensin-converting enzyme for the treatment of hypertension and proteases involved in the proliferation of the human immunodeficiency virus.

New findings in the area of parasite cysteine protease inhibitors may lead to a fuller understanding of these agents and how they can be used effectively. These few examples indicate what parasitology can contribute to general biomedical research when thought of, used, and appropriately dissected as model systems. As mentioned above, because these systems often push biological mechanisms to their limits, they can be expected to continue to yield future insights into fundamental areas of molecular biology, cell biology, and immunology.

If parasitology is to continue to provide new, exciting insights into the world of biological mechanisms and biomedical research, its investigators must take full advantage of the newest tools and approaches available, and work hard to adapt them to their needs and questions. As investigators have striven to do so with certain protozoans over the last years, they must now forge ahead to develop models that include a wider spectrum of parasites.

The genome sequencing programs under way with various protozoans and helminths are a clear indication of the intent of investigators in this field to move forward. Because of its obvious public health importance, work on the P. The initial push will certainly be to use these tools for drug target and vaccine target discovery, but the yield will also be in areas of basic understanding of the genetics, biochemistry, cell biology, and even epidemiology of the organisms.

Helminth genomics has struggled to develop apace, and now, with the completion of the Caenorhabditis elegans genome sequencing The C. Trematode genomics is beginning to take shape with recent renewed interest in Schistosoma mansoni Le Paslier et al. The incipient development of DNA microarrays to detect gene expression of P. These technologies will clearly contribute greatly to the ability to detect expression under multiple conditions of interest. Initially these are likely to yield profiling or "fishing" expeditions, but those will be useful in laying the ground work, and hypothesis-driven studies will soon follow as the techniques are further developed and made more readily available to a larger number of investigators.

The vast development of immune cell markers, transgenic and knockout hosts, recombinant immune components, such as cytokines, che-mokines and their receptors, and monoclonal reagents have made experimental and human immune studies much more wondrous and amazing. Much of this work is still in the dissecting phase, where the amount of information generated is far ahead of our true understanding. Yet even so, important insights have been made. The future will rest on the effective use of genomics, reverse genetic analysis, proteomics and bioinformatics.

The list of parasitic diseases that are known to pose serious public health problems often depends on where one is on the globe and can, of course, be debated by scientists and public health officials. However, in general, which ever candidates make one's final list, the picture is long and sobering Table I. Yet major advances against these scourges have been made, are currently being made, and will continue to be made to an even greater degree in the 21st century. How has this occurred thus far, and how will it progress in the future?

The path is not a simple one. It is a long and winding road that begins with scientific discovery and understanding, leads to tool development and comprehension of how best to use these tools, and progresses on to policy and decision making, implementation and management.

Throughout this entire process the need for scientific research continues, but the nature of that research effort changes and refocuses as the process moves ahead. So where are we now in the world of curtailing morbidity and mortality caused by parasitic diseases?

Parasitic diseases: opportunities and challenges in the 21st century

First, I should define what I mean by the various levels of limiting parasitic diseases or their consequences. The entry level of such programs is control. The term control implies that through deliberate efforts we can decrease transmission or severity of a given infection, and that the implementation of this ability will need to be an ongoing activity for the foreseeable future. Examples of diseases that are currently thought to be, with sufficient effort, controllable are malaria and the soil-transmitted helminths.

Elimination of a disease is the next step past control. This means that appropriate implementation of the available tools can reduce the incidence of the disease in people not necessarily other host species to zero. Some have also inserted in this definition the phrase "as a public health problem". This then might apply to a zoonosis that no longer threatens people, but continues to be transmitted among other potential reservoir hosts. Elimination of an infection either complete or as a public health problem is defined as removing the threat of infection to a level at which it is no longer transmitted, but from which it could return.

In the case of elimination, surveillance for a re-emergence of the disease is still needed, but further efforts at elimination are not warranted unless surveillance detects the occurrence of cases. The next level of such activities is eradication. Full eradication is the permanent reduction to zero of the global incidence of a disease. Once accomplished, neither further prevention nor surveillance are needed.

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In theory, an infection could be eradicated and yet the organism that causes the disease could be housed in a secure condition. To carry eradication to its full and logical conclusion, the total expungement of the organism responsible would require a further step, that is the extinction of that species. In addition to these strict definitions of control, elimination and eradication, it is possible to think of them as being applied to a given geographic area. Thus, elimination of polio has been achieved in the Americas, yet imported cases do still occur, so continued immunization must continue.

When polio is eradicated from the world, as smallpox has been, there will no longer be any need to be immunized against polio, or to maintain surveillance for cases of polio. Similarly, India, once the country with a high number of cases of dracunculiasis Guinea worm disease , has now been certified by the International Commission for the Certification of the Eradication of Dracunculiasis as having eradicated this debilitating infection Holden Table II outlines some aspects of the problem that must be considered to be able to make such a momentous decision.

The combination of appropriate tools, and the ability to use them in an effective and cost-effective manner must be coupled solidly to both the availability of sustained funds for the job, and the will to do the job. It bears remembering that the cost of a bad decision, that is, one based on an inappropriate strategy or mis-reading of public support, is very high, and can result in major adverse consequences for other fledgling or future efforts Cochi et al.

I think it is useful, before I discuss the future of such programs, to remember that several control, elimination and even "geographically defined eradication" campaigns against parasitic diseases have been highly successful over the last century. For example, through both dedicated campaigns and eventual rising standards of living, both the United States and Japan have very successfully eliminated geohelminths and malaria as major public health problems.

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Even more dramatically, again through highly organized campaigns, Japan "geographically eradicated" both filariasis and schistosomiasis. Another extraordinary achievement in the realm of elimination of a terrible disease is proceeding in Brazil, Argentina, Uruguay, Paraguay, and Chile. This outstandingly successful effort has almost totally eliminated domiciliary transmission of Chagas disease to humans in many parts of the region.

It is a remarkable tribute to those involved, the countries involved, the Pan American Health Organization, and the World Health Organization. Similar campaigns in the Andean and Central American regions have begun, but face some challenges that again point out the parallel need for continued research efforts with all implementation programs. So where are we at this time in regard to such programs against parasitic diseases? Table III lists those major programs that are now ongoing at one level or another, as well as examples of proposed target diseases for future independent or integrated campaigns.

The discussion of the independence vs integration of control, elimination, or eradication programs is beyond the scope of this presentation, but it is one that will need to be examined effectively in the future.