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Understanding how resistance develops and what factors play a role is crucial to avoid it to happen or to deal with it when it is already there. This understanding requires  knowing the basics of genetics and population dynamics of the parasites.

DNA molecule, the carrier of genetic information the cellsA crucial aspect on resistance development: it is a matter of parasite populations, not of individual parasites. A parasite is born resistant or non-resistant (i.e. susceptible); it is resistant or it is not resistant, but it does not develop resistance itself. It is the population that develops resistance. In a completely non-resistant population, no individuals are resistant. In a completely resistant population all individuals are resistant. In a strongly resistant population many individuals are resistant (instead of all individuals being strongly resistant). In a weakly resistant population a few individuals are resistant (instead of all individuals being weakly resistant).

Unfortunately it is necessary to get into a few complex biological aspects of cell biology and genetics to understand resistance development. Some terms explained below are used in other articles on resistance in this site. I have tried my best to summarize the topic for non-specialists. But to keep it simple simplifications are unavoidable.  Biology is always more complex than expected. Usually there are as many exceptions as rules... This is why it is so fascinating.


Genetic variability of parasite populations

In populations of ticks, fleas, flies and all other parasites it happens the same as with human populations: not all individuals are absolutely equal. There is a natural variability of the biological features. Some people have blue eyes, other green eyes, other brown eyes. Some people are dark-haired, other fair-haired, etc. These features (eye color, hair color) are the expression of the genes of each particular individual.

The genes are the molecular units of heredity but also of the features of each individual, e.g. eye color, hair color, etc. A gene contains the genetic code that that will produce a particular feature in a given cell or group of cells in an organism. This genetic code is chemically "written" in molecules of DNA (deoxyribonucelic acid). All individuals of the same species share a "fixed" package of genes called the "genome". In each individual the same gene (often more than one) determines the color of the eyes, but this same gene is slightly different in a person with blue eyes and in a person with brown eyes. This happens for most genes in each species. This genetic variability occurs in all living organisms, also in parasites.

Most cells of all living organisms contain the whole genome, usually two copies of it (such cells are diploid). One copy is inherited from the mother, one from the father. This means that there are usually two copies of each gene in each cell (each copy is called an allele). If both gene copies (allele) in a cell code for the same feature, e.g. blue eyes, the individual will have blue eyes. It is said to be homozygotic (for blue eyes). If both gene copies code for a different feature (e.g. blue and brown eyes), the individual is called heterozygotic for this feature. In this case it can happen that one copy is dominant, i.e. stronger that the other one that is called recessive. It can also happen that both are equally strong and are called co-dominant.

Let's come back to resistance of parasites to parasiticides. Populations of parasites develop resistance because some individuals are naturally resistant (or tolerant) to parasiticides, i.e. some of their genes are slightly different to those of other individuals, and these genes make them capable of surviving an exposure to parasiticides that would kill most other individuals of the same population. This natural resistance is just there in a few individuals, even if they were never exposed to parasiticides. In natural populations never exposed to parasiticides, these naturally resistant individuals are mostly very rare, perhaps less than 1 in a million individuals. This can be due to the fact that the feature of being resistant to parasiticides has no reproductive advantage in absence of exposure to the parasiticide. It can even be linked to some reproductive disadvantage, because most genes do not code only for one feature, but for several ones.


Gene mutations

Mutations are molecular modifications of the genes that are at the origin of the variability of the individual characters in a population.

The genetic information of most organisms (including vertebrates, insects, worms, etc.) is determined by the genes it receives from its mother - through the ovule, or female gamete - and from its father - through the sperm or male gamete.

Most somatic cells of most living organisms contain two copies of the whole genome: they are called diploid. This means that each cell contains also two copies of each individual gene, because during cell division (mitosis) the whole DNA of a cell is duplicated and each daughter cell becomes one copy of the whole DNA.

In contrast with this, the germinal cells, i.e. the gametes (ovules and sperms) have only one genome copy. They are called haploid. This is because during gamete production there is a special cell division called meiosis (instead of mitosis) after which each daughter cell receives only one instead of two copies of the genome, i.e. each resulting cell becomes only half of the DNA contained in the mother cell. This special meiotic division is a key moment regarding genetic variability.

The reason is the following. All somatic cells keep each one of the maternal and paternal copies of the genome separated, i.e. "unmixed". Imagine the genome as a bus, and the genes in the genome as passengers in the bus. A somatic cell would contain two buses, each with it's own passengers. Before dividing, the mother cell duplicates each bus with its own passengers. During division (mitosis) it distributes the bus copies in the daughter cells in a way that each daughter cell gets a duplicate of both buses, each with its own passengers, without mixing the passengers of each bus. Meiosis in germinal cells is completely different. The mother cell does not duplicate the buses, but gives one single bus to each daughter cell. BUT, before completing division, some passengers change the bus. As a result, each germinal cell (male or female) will get only one bus (one genome) filled with passengers (genes) that are differently mixed than in the mother cell. Which passengers (genes) change bus (genome) is determined by complex molecular and genetic factors. Sorry if this comparison is not very helpful...

Upon meiosis in the germinal cells errors can occur during the separation of both DNA molecules that constitute each genome. These errors are called mutations, meaning modifications of the original molecular structure (or sequence) of the genes. Some external factors are mutagenic, i.e. they induce the appearance of such mutations, e.g. UV radiation in sunlight, radioactivity, certain chemicals, etc.

Mutations, i.e. errors during the cell division can happen also on somatic cells. The essential difference is that mutations in germinal cells are transmitted to the offspring, whereas those in the somatic cells are not.

Mutations, whether those that occur spontaneously or those induced by mutagenic agents, are mostly lethal, but usually recessive. This means that the sound gene copy in the diploid genome takes over and ensures survival of the cell or organism. If the lethal mutation is dominant the cell or organism will die. But some mutations are not lethal, they just modify the gene. E.g. a mutation of the gene that codes for producing a red pigment may just not work and result in a white color. If an organism has one gene copy coding for red and another copy coding for white, the result may be pink. The offspring of two organisms that are homozygotic for red color will all be red. But the offspring of two organism that are heterozygotic for red and white will be 25% red, 50% pink, and 25% white.

Coming back to resistance development, mutations are at the origin of the genetic variation among the individuals of a parasite population. What it is not yet elucidated is whether exposure to parasiticides induces such mutations that make the parasites resistant, or whether such mutations were already present in the population before exposure, or both.


Resistance development is a particular case of natural selection

Resistance development in parasites is a special case of the same "natural selection" that drives evolution. It is questionable whether "selection" in this case is "natural" or not, because the massive application of parasiticides is not something that occurs in nature but is done by human action. However, from the point of view of the parasites, it doesn't matter where the parasiticides come from.

If you expose a parasite population to a parasiticide long enough, only those parasites will survive that carry the mutation(s) that makes them resistant to such exposure. After several years the whole population will be resistant, because only resistant individuals were allowed to survive and reproduce.

In fact, development of resistance is very similar to what most farmers can do with livestock. If a farmer wants to get tall cattle, he will use only the tallest cows and the tallest bulls for breeding. And he will repeat the process with the offspring until he gets the expected animal size. At the end the whole herd (i.e. the population) will be taller. Small cows and small bulls just don't get the chance for breeding.

When a cattle herd or a sheep flock is treated with a parasiticide, the parasite population that colonizes such herd or flock is put under selection pressure, a brutal selection pressure. If only 10 in a million parasites are initially resistant because they carry a particular mutation, probably all will survive and breed with a few other susceptible parasites that have also survived because they were not reached by the parasiticide for whatever reason. In the surviving population maybe 100 parasites in a million are resistant. If this population is again exposed to the same parasiticide, the same will happen and in the surviving population resistant parasites may be already 1000 in a million. If the selection pressure is kept long enough, only resistant individuals will survive and the whole population will be resistant.

This happens with any parasite, whether veterinary or human parasites, as well as with domestic and crop pests: insects, ticks mites, worms, fungi, weeds, rats, etc. And it is exactly the same for bacteria, viruses and other microorganisms that cause diseases in humans, animals and crops.

In addition, parasites can develop resistance not only to synthetic chemicals, but also to natural chemicals, vaccines and whatever puts them long enough under selection (or selective) pressure.

Once a parasite population has become resistant to a given parasiticide, if the selection pressure stops, the degree of resistance usually decreases. But the experience is that even after decades without selective pressure, the resistance genes remain in the population. If the same parasiticide is used again, resistance will come back significantly faster than the first time, usually with 2 to 3 years or even shorter.

Experience also shows that development of resistance to a given parasiticidal active ingredients is basically independent of the delivery form. E.g. horn fly resistance to synthetic pyrethroids developed in countries that used mainly insecticide-impregnated ear-tags but no dips, sprays or pour-ons, in countries that used mainly pour-ons but no ear-tags, in countries that uses only dips or sprays, etc. The only difference is that some delivery forms will build up a stronger selection pressure, which usually results in a faster development of resistance.


Selection pressure

Selection pressure is the most determining factor for resistance development. Treating animals repeatedly with parasiticides has the unavoidable effect of selecting those parasites with resistance genes that allow them to survive the treatment. No treatments, no selection, no resistance development. 

It must be always kept in mind that not the single parasite is important, but the population it is part of. Not an individual parasite becomes resistant, but a population. Selection pressure selects individual parasites in the population that have specific gene mutations that make them resistant to the mechanism of action of a parasiticide. 

A parasite population is basically a group of parasites that remain in a certain "territory" where they find food and complete their life cycle. Ticks that infect cattle in a particular property are a population, or mites that infect chicken in a poultry-house, or fleas the infect dogs in a village, etc. If the parasites can easily disseminate (e.g. flying insects), populations may occupy larger areas.

The stronger the selection pressure is, the faster resistance will develop. In practical terms, this means that the more parasiticidal treatments are done within a parasite season, or the higher the concentration of the product, or the more animals within a property are treated, the higher will be the selection pressure. Provided that the mechanism of action of the parasiticide used remains the same.

It is important to know that many parasiticidal treatments approved for and used only against one parasite species, put other parasite species also under indirect selection pressure, regardless of whether the products used are approved or not against such parasites. If they contain broad-spectrum active ingredients (e.g. organophosphates, synthetic pyrethroids, macrocyclic lactones, fipronil, etc.) they will have a certain level of efficacy against several un-targeted parasites and exert selection pressure on them. A typical case are cattle pour-ons approved only for horn fly control, or only for cattle tick control, etc. Such products will exert some level of selection pressure against all parasites that infect cattle at the time of treatment, regardless of whether they are approved or not against such parasites. Treating crops with pesticides against their own specific parasites may also exert indirect selection pressure on veterinary parasites whose ecosystem is reached by such pesticides. This is the case of several species that breed on water (e.g. mosquitoes, black flies, etc.) that is polluted by pesticide run-off after rains, floods, etc.

Refuges

A key factor regarding selection pressure is the presence or not of refuges where some parasites of a population are not reached by the parasiticidal treatment. The reason is that parasites in such refuges are not selected for resistance. But since they are part of the population, they will mate with the selected survivors of the treatments and "dilute" the resistance genes in the selected population, which are mostly recessive. This slows down the development of resistance. The larger the refuge, the stronger the dilution factor, the slower resistance will develop.

Wildlife is often a natural refuge for many parasites. This is the case for some tick species (e.g. Amblyomma spp, Rhipicephalus spp, Ixodes spp), horse and deer flies, stable fliestsetse flies, screwworm flies, etc. Since wild animals are not treated with parasiticides, all those parasites that live or feed on them are not selected for resistance. Such wild animals are often reservoirs of parasites for domestic animals in many properties and may be undesired for this reason. But their role as parasite refuges that stem the development of resistance is often underestimated.

In fact, the parasites with more serious resistance problems are those that are quite host-specific, e.g. the cattle tick, Rhipicephalus (Boophilus) microplus and horn flies (Haematobia irritans) that attack almost only cattle, or sheep lice (Damalinia ovis) and that are sheep-specific. In other cases, although parasites can feed and/or complete development on other hosts than domestic animals, such alternative hosts are simply not available, or are too scarce. This is the case in many confined operations (e.g. for poultry, dairy farms or swine), but also in grazing livestock in properties with scarce or no wildlife at all.

Duration of the life cycle

A key factor in resistance development is the duration of the life cycle of a parasite. The reason is that the shorter the life-cycle is, the more generations will follow during a season, and the faster the selection of resistant mutants will take place in the population. Duration of the life cycle is driven mainly by species-specific biological factors, by climatic conditions (mainly temperature and humidity) and by availability of food.

Most parasites with serious resistant problems have a relatively short life cycle, between a week and a month. In a suitable environment such parasites may have 20 and more generations a year and are capable of developing resistance after 2 to 3 years of continuous exposure.

As a general rule, most parasites develop faster under the warm and moist conditions that prevail in tropical and subtropical countries. But many confined operations (poultry, swine, dairy) often allow year-through parasite breeding, even in regions with cold winters.

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