The Mighty Vector: Role of vector ecology in virulence evolution. Nitesh Vinodbhai Pandey , Researcher, Indian Astrobiology Research Centre, Mumbai, India. Address correspondence to Nitesh V. Pandey,
[email protected]
Abstract: Ewald has suggested that the vector-‐borne diseases should evolve to be more virulent than the diseases transmitted directly. I have argued in this paper that the fundamental assumptions of Ewald's model regarding the vector-‐borne diseases are flawed and are also the root cause of its discrepancies. I have refined Ewald's trade-‐off model of Virulence evolution by incorporating the insights from vector ecology. The vector-‐parasite system of Aedes aegypti and dengue has been selected to demonstrate the strong role of vector ecology as a major determinant of virulence evolution. I have also shown that the Darwinian fitness of parasite variants, be it mild or the virulent one, would depend on ecological aspects of the vector. A thought experiment has also been proposed to illustrate this improvised model of virulence evolution. Keywords: Trade-‐off model; Virulence evolution; Vector-‐borne diseases; Dengue epidemiology
1. Introduction: What according to you is the most important thing that should regularly happen in Science? If you had to take my opinion, I would have certainly gone with “Debates”. Yes, Debates must regularly take place in science as they are at the very core of its foundation and are required for its progress. Nobody within the Evolutionary Biology fraternity would have ever imagined that a fellow researcher's (Ewald) fateful bout of diarrhea would usher a productive debate regarding virulence evolution of infectious diseases [1]. Ewald asked some interesting questions about the nature of his diarrhea symptoms, which he got while working on a research project near garbage dump on the outskirts of Manhattan, Kansas [1]. This experience inspired him to think about the disease from the pathogen’s perspective. The application of evolutionary insights he derived from this incidence helped him to formulate his trade-‐off model of virulence evolution [1]. Ewald proposed that the difference in severity of the infectious diseases could be understood from their different modes of transmission [1]. He suggested that parasites often have variants, which differ in terms of their virulence. The Darwinian fitness of these pathogenic variants
would depend on the modes through which they are transmitted from an infected host to the susceptible one [1]. Ewald suggested that for a disease, which is transmitted directly, the virulent pathogenic variant that can make the human host too sick or bedridden would have least chances of reaching to a new susceptible host. This meant that directly transmitted diseases would evolve to be mild since the milder variants would out-‐compete the virulent variants in terms of transmission. They would also have higher Darwinian fitness. However, if there are vectors to spread the virulent variants of diseases from one host to another, the pathogen can afford to be deadly and exploitative as the cost paid for the resulting severe sickness is less. In short, the vector-‐borne diseases would evolve to be highly virulent because they have to pay lesser cost for the diminished mobility of the host that results from their excessive exploitation. In spite of its intuitive appeal this model has been criticized on various grounds so far. The following paragraph deals with the exact issues of Ewald’s model in detail.
2. The problem: Contrary evidence for the majority of the vector-‐borne diseases.
In contrary to what Ewald has predicted, most of the vector-‐borne diseases are either mild or asymptomatic in the majority of the infected cases. There are in fact diseases like River blindness [2], Zika [3] and Chikungunya [4], which in spite of being vector-‐borne rarely kill their host. Even diseases like Dengue [5] and Malaria [6] cause severe symptoms in a very small portion of the total infected population. The extreme cases that we observe in such diseases are nothing but the tip of an iceberg. Ewald's model and the overall trade-‐off theory of virulence evolution have been widely challenged since last 30 years mainly for its lack of evidence. Most of these authors who have challenged the model have pointed towards various shortcomings to justify the observed discrepancies. Their respective arguments are as follows: 1. Trade-‐off model is over simplistic [7]. 2. The biological details of parasite's life history and disease etiology were never considered within the model [7]. 3. The role of immune response in causing disease was overlooked [8]. 4. There is ambiguity over the definition of virulence. Morbidities like Anemia, Weight loss and infertility should also be considered as a measure of virulence apart from host death [7]. 5. There might be no correlation between excessive replication of the parasite and virulence. A trade-‐off between Virulence and transmission might be completely absent in some vector-‐borne diseases [8]. For a vector-‐borne disease with no correlation between higher replication rates of parasites and virulence, it is justified that such diseases can be mild. However, How can we justify the mild and asymptomatic nature of Dengue and Malaria in the majority of the infected cases? Although we have a clear evidence that a
virulence-‐transmission trade-‐off exists for both of these diseases [9,10]. As per Ewald's model, Dengue and Malaria should have been highly virulent in the majority of the cases. This theory and empiricism mismatch for the vector-‐borne diseases have led some researchers to doubt the potential of the trade-‐off model [7]. This is certainly not an encouraging situation and demands a resolution for sure. In the following section, I have argued that the fundamental assumptions of Ewald's model for the vector-‐borne diseases are unnecessary and flawed. These assumptions are also the root cause of discrepancies in his model. I have also offered a resolution that will make his model more robust and would also address the major discrepancies.
3. The Solution: Incorporating insights from Vector-‐ecology to make Ewald's model more robust.
I would like to use the case of the Dengue vector Aedes aegypti to prove my following claims i.e 1. Ewald's assumptions for the vector-‐borne diseases are flawed 2. Insights from Vector-‐ecology can improvise his trade-‐off model of virulence evolution. In the following Section, I will be presenting my arguments against the fundamental assumptions of Ewald regarding virulence evolution among the vector-‐ borne diseases. 3.1. Flawed Assumption 1: Mobility of the host is not important for the transmission of vector-‐borne diseases because vectors can transmit the virulent variants of the parasite from the immobile host to susceptible one [1]. For the above assumption to hold true it would require that the vector is highly mobile so that it could travel long distances to spread the disease from a bedridden severely sick host to a new uninfected host. However, here comes an important twist. The Aedes aegypti vector that transmits Dengue is very lazy and sessile. This vector has a mean dispersal rate of 50m and maximum dispersal of 100m [11]. It stays in only one home for the entire lifespan. The vector density is in fact so low that there is sometime just one Aedes aegypti mosquito for the entire house [12]. The infection rate of Aedes aegypti even in the endemic areas is as low as 1% [13]. In such cases, a vector-‐borne disease can spread or perpetuate only if the host is mobile enough to infect the new vectors so that the transmission cycle could continue. Therefore a vector-‐borne disease that causes acute illness and limits the mobility of host would easily go extinct if both the vector and the host have restricted mobility. This has serious implications for virulence evolution among those vector-‐borne diseases for which there exists a trade-‐off between virulence and transmission. I would like to explain this claim of mine from the following thought experiment:
Imagine that there are two best friends, Sam and John. Sam is infected with a mild variant of Dengue virus whereas John is infected with the virulent variant of the same virus. Since Sam is infected with a mild variant he will be asymptomatic and mobile but John who is infected with the virulent variant will be bedridden and severely sick. The severely sick host John has a probability of being bitten by the mosquitoes of his own house only, whereas the mobile host Sam has a probability of being bitten by mosquitoes of every home he visits, be it his friend’s or relative’s. Sam can also infect many Aedes aegypti mosquitoes at cluster regions like Shops and markets where Aedes aegypti density might be bit higher. This means that the mild variants of Dengue virus would be transmitted far more than the one, which are virulent. The Darwinian fitness of variants causing mild disease would be much higher over the virulent ones. Therefore a stable evolutionary strategy for any such vector-‐borne parasite would be to cause a mild infection because it significantly enhances their transmission benefits. This would eventually lead to decrease in virulence of the disease with time in contrary to what Ewald had predicted in his model. The following is a visual representation of my thought experiment: Figure 1: Thought Experiment on the role on vector ecology in virulence evolution in dengue.
3.2. Flawed Assumption 2: The higher virulence of the vector-‐borne parasite is adaptive as it makes the reservoir host less defensive towards vector bite and therefore facilitates transmission [1]. The explanation offered for assumption 1 equally proves the fallacy of this assumption too. However, it is important to trace the roots of this assumption. Ewald had derived this assumption from a study done on mice, which concluded that mice with a higher magnitude of malaria parasites were more susceptible to mosquito bites compared to the mice that were diseases free [1]. Similar animal studies for Dengue were also cited to support this assumption [9]. The conclusion of these animal studies that more aggressively replicating strains incapacitate the host and would have higher chances of being transmitted does not apply to the real world scenario. In reality, the virulent strains of Dengue cripple the mobility of the host and hinder the process of transmission. These laboratory models of the vector-‐borne diseases hardly capture the real world complexity of human host, mosquito vector and parasite interactions and therefore the generalization derived from such studies have resulted in discrepancies. I would also like to challenge Ewald’s view that higher virulence is adaptive for vector-‐borne parasites because it facilitates transmission. The following is my critique: We usually defend ourselves from something we know would do us harm or would attack us in some way. What if we are attacked in a way that we do not even realize? Aedes vector employ this exact strategy to bite their host. The Aedes aegypti vector mainly bites at the ankle, which is one of the safest regions to bite [14]. The biting of the mosquito also often goes unnoticed [14]. I do not think that any change in behavior that makes the host less defensive towards the mosquito bite is required because mosquitoes already have adaptations that serve the same purpose. I would like to make similar arguments for the primary Malaria vectors i.e Anopheles gambiae and Anopheles funestus. Both of these vectors have their peak biting time in the midnight when the human host is in deep sleep and inactive [15]. Be it sleeping human host or the sick one lying on the bed, both are equally incapable of defending themselves from the biting mosquitoes. The malaria vectors like the ones of dengue are also known to bite at the ankles [15]. In the following section, I would like to show the utility of applying the insights from Vector-‐ecology to Ewald’s trade-‐off model of virulence evolution.
4. This new model that integrates the ecology of the vector with Ewald's conventional trade-‐off model has two natural predictions to offer:
1. The mobility of the host would be very important in the transmission dynamics of dengue. 2. Majority of the dengue cases would be asymptomatic in the host. However, these asymptomatic hosts would have enough viremia to infect the biting mosquito. I would like to present pieces of evidence available from dengue endemic regions to support the above two predictions of this new model. 4.1. The role of human movement in transmission dynamics of Dengue: Recent evidence from the field studies of dengue endemic regions has concluded that in the absence of movement of the human host the dengue transmission cycle would collapse [16]. The regular infection of new Aedes aegypti mosquito by the viremic human host is what drives dengue epidemic and not vice versa. Results from a recent study on Dengue epidemiology also indicated that the human movement alone could explain significant spatial variation in urban transmission rates of Dengue [16]. A study in Thailand that used DNA fingerprinting to track the feeding behaviour of Aedes mosquitoes concluded that frequent and heterogeneous biting by Aedes aegypti on residents and transient visitors and mosquito feeding/transmission hotspots are important entomologic features of dengue epidemiology [17,18]. Padmanabha et. al also concluded that human social behaviour and demography drive patterns of fine-‐scale dengue transmission in endemic areas of Colombia [19]. A Cambodia based study also suggested that human movements could only explain the heterogeneous propagation of dengue infection [20]. Studies done in dengue-‐endemic countries like Thailand and Peru have concluded that the fine-‐scale movement of the reservoir hosts is the major driver of dengue [21]. These studies also implied that the geographical spread of the dengue is not possible without the movement of dengue carriers [21]. The overall engagement of people in their regular and daily routine determines their exposure to the insect vectors and plays a very important role in the dynamics of pathogen transmission [21]. Stoddard et. al based on their activity space model concluded that dengue is mostly transmitted when people are mobile as well as are engaged in their daily activities. Reiner et.al have shown that it is the friends and relatives of the infected dengue subject who have much higher chances of getting the secondary infection and not their neighbours [22]. This argument is derived from a simple logic that the most probable places that any infected but mobile host will visit are its social contacts. This has been rightly named as the Social contact hypothesis proposed to explain the Dengue epidemiology [22].
Stoddard et al. in their brilliant paper have emphasized the role of human movement as a major driver not only for dengue but also for most of the vector-‐ borne diseases [21]. The patterns of the human movement are the most important determinant of vector exposure and therefore they must be considered in every study done to understand epidemiology of vector-‐borne diseases [21].
4.2. The asymptomatic hosts are capable of infecting mosquitoes as well as they constitute the majority of the dengue cases: Three-‐quarters of the estimated 390 million dengue virus (DENV) infections each year are clinically in apparent [23]. People with asymptomatic dengue virus infections were generally considered dead-‐end hosts for transmission because it was assumed that viremia in such carriers would be too low to infect the biting mosquito. The recent field studies have presented a different picture though. Despite of their lower average level of viremia, people with inapparent infections can be infectious to mosquitoes [24]. Moreover, at a given level of viremia, a dengue virus infected person with no detectable symptoms or before the onset of symptoms is significantly more infectious to mosquitoes than people with symptomatic infections [24]. This is because people infected with dengue without clinical symptoms may be exposed to more mosquitoes through their undisrupted daily routines than people who are severely sick. The asymptomatic hosts represent the bulk of dengue positive infections; data collected from recent dengue studies indicate that the asymptomatic reservoir hosts might be significantly contributing to regular virus infections of mosquitoes than previously recognized [24]. A variety of the cohort studies done to understand the transmission pattern of dengue in endemic countries like Thailand [25-‐29], Indonesia [30,31], Nicaragua [32], Vietnam [33], Peru [34,35] and India [36] have supported the strong role of asymptomatic cases in the spread of dengue. These studies have also concluded that the transmission dynamics of dengue can be heterogeneous in nature both temporally as well as spatially. Studies that have incorporated geographical cluster designs to understand dengue transmission also support the role of asymptomatic dengue carriers in its transmission to a substantial level. [37,38,39] A recent study in a Leishmaniasis endemic region also found that the asymptomatic cases are far more prevalent than the symptomatic cases [40]. A future study in the Visceral Leishmaniasis endemic region could confirm the role of asymptomatic carriers in the transmission cycle of this disease too. A study done to understand Malaria epidemiology confirmed that the asymptomatic carriers not only are in significant majority but they also infect the Anopheles mosquito. The asymptomatic malaria carriers therefore contribute in the transmission of the protozoal disease in a major proportion [6].
4.3. Dengue Mathematical Models to support the importance of host mobility in Dengue transmission: Apart from studies collecting data from dengue endemic regions there are simulations and mathematical models that have emphasized the role of host movement as a mandatory requirement for dengue transmission. [41,42]. One of the studies that analyzed the trade-‐off between host immune response and levels of arbovirus viremia suggested the following relation: the strains of arbovirus that can keep ‘low profile’ in the vertebrate host and maintain viremia for a longer period of time would have maximum transmission benefits and therefore also Darwinian fitness. The study also implied that the strains producing the higher magnitude of viremia get cleared by the immune system quickly and rarely get transmitted [43]. These results have some important implications for the virulence evolution in case of dengue as well as for other vector borne diseases where the mobility of the reservoir host is equally important for transmission. 4.4. The problem with the evidence of transmission-‐virulence trade-‐off in dengue: There have been many studies that have confirmed a trade-‐off between transmission and virulence for dengue infections. The following are some important and common conclusions of these studies: 1. Dengue virus variants, which reproduce aggressively and lead to higher viremia are more virulent. There have been multiple independent studies that have confirmed a correlation between higher viremia titer with dengue severity [9]. 2. Laboratory studies on dengue serotype 2 have found that genotypes that are more virulent to humans also more readily infect mosquitoes and human cells. Elevated human viremia is then supposed to increase the chance of transmission to mosquitoes [9]. 3. It has been suggested that people harbouring more virulent parasites may be easier prey for mosquitoes, thereby increasing the frequency of being bitten. Some authors have also suggested that the biting rate increases with virulence to humans [9]. All these studies that have correlated virulent strains and their higher infectivity for mosquitoes have one common drawback. These studies were performed in artificial laboratory settings and were based on animal models. Data from artificial blood meals suggest that arboviruses would have to reach quite high titers in vertebrate hosts before significant transmission could occur. However, this inference may not be true because the threshold for transmission of a given arbovirus is substantially lower when a vector feeds on a living vertebrate host
rather than an artificial meal [43]. In fact, the same authors have also pointed out that in case of higher viremia the overall infectivity of the host for the biting mosquito may decrease because of the host immune response [43]. Also, none of these studies considered the important ecological aspects of Aedes aegypti like its limited dispersal, very low density and low infectivity. This is the reason we do not find proof for Ewald’s prediction in case of vector-‐borne diseases. In reality what we observe is that the mild strains are more infectious to the mosquitoes. They also get more bitten by vectors because the infected host is mobile and can visit new places having their own vectors. The insights from vector ecology when integrated with Ewald’s trade-‐off model offers a picture that is much more realistic epidemiologically.
5. Can insights from Vector ecology of Aedes aegypti also explain the epidemiology of Chikungunya?
The rationale of this refined trade-‐off model also applies to other diseases transmitted by Aedes aegypti mosquitoes like Yellow fever, Chikungunya and Zika. Yellow fever and Zika are asymptomatic or cause mild illness in the majority of the infected individuals. Chikungunya unlike dengue and Zika causes symptoms like high fever and severe joint pain in more than 80% of the cases and therefore severely cripples mobility of the host. This new improvised model suggests that Chikungunya would always be a clustered disease confined to smaller geographical regions. This is because the disease has a negative effect on host mobility, which we know is important for transmission [44]. This model therefore also explains why Chikungunya occurs in small clusters of a limited region of 300 meters unlike wider local spread of dengue. The outbreaks of Chikungunya are also sporadic. A study done to understand the transmission dynamics and distribution pattern of Chikungunya outbreak in a village of Dhaka, Bangladesh came at the following conclusions that perfectly fit with this refined trade-‐off model of Ewald [44]. The following were the conclusions of this study: 1. The risk of getting infected with Chikungunya significantly dropped for people living 50m away from the household, which had positive cases [44]. 2. Females were 1.5 times more likely to become infected than males, which was virtually identical to the relative risk of being at home estimated from an independent human movement study in the country [44]. I would like to predict that the local spread of Chikungunya would never be as intense as dengue because of its severe symptoms that hamper the mobility of the host. In future, if we find Chikungunya to spread in the endemic locations with similar intensity to that of dengue then it will mean that there are a lot of asymptomatic cases of Chikungunya too and they also go undetected. Based on the insights of this improved trade-‐off model of Ewald we can categorize any vector-‐borne diseases in terms of their potential to quickly spread within
geographical regions. This would be a very powerful tool as it might help us in predicting as well as controlling important vector-‐borne diseases.
6. A general refined trade-‐off model of Virulence Evolution: Integrating Vector ecology with Ewald’s model.
The disease vectors are highly diverse in various aspects like their flight range, density, lifespan, vectorial capacity and biting time. These different facets of vector would affect the virulence evolution of every concerned vector-‐parasite system differently. However, the most important determinants of virulence evolution are vector’s flight range and contact rate with the host. The following table covers the diversity among the vectors of the most important human diseases. Table 1: Disease vectors and their diversity.
It is clear from the case of dengue that the insights from vector-‐ecology can make Ewald’s trade-‐off model much better. The question that naturally arises is that if using the similar insights from other disease-‐vector systems, could we also build a general model that offers testable predictions for them too? The answer would be yes. The following are some general predictions on the virulence evolution of vector-‐borne diseases based on this improvised model. The model can predict about the relative Darwinian fitness of the milder and the virulent variants for a disease having a trade-‐off between virulence and transmission. The predictions are as follows: 1. The Darwinian fitness of the mild strains of the parasites would be higher for a disease in which mobility of the host is important in transmission dynamics. The mobility of the host is crucial for a disease that is transmitted by a vector with the following features: a. very limited dispersal, b. low infectivity and c. low density. Ex. Aedes aegypti and Sandfly. In case of a disease transmitted by a sessile vector with very limited dispersal and infectivity, it is the mild parasite strains that will have higher Darwinian fitness, which would also easily outnumber the virulent strains that make the reservoir host immobile because of incapacitation. The following figure captures some very important ecological aspects of Dengue vector Aedes aegypti: Figure 2: Important ecological features of Aedes aegypti
2. In certain special cases mobility of the host might also be required even if the vector can travel or disperse for longer distances. The following are the traits of vector that would also lead to higher Darwinian fitness of mild parasitic strains: Vector has not only low density and infectivity but it also has a very low contact frequency with the reservoir host. In such cases since the contact of the vector and host are very limited the perpetuation of the transmission cycle would sustain only under any of the two conditions. 1. Vector has a very long lifespan of at least some months or a year 2. The reservoir host suffers from a chronic infection and has enough parasites in the blood to infect the vectors for years or at least months. This would ensure that the new vectors are regularly infected to keep the transmission cycle going. Ex. Tsetse fly that transmits the trypanosomes to humans and animals to cause Human African trypanosomiases, commonly called as Sleeping Sickness [45]. The tsetse fly has a longer flight range and dispersal rate but its frequency of contact with the human hosts is still very less. Therefore long flight range is not much of use in disease transmission here [46,47]. To make the situation worse, the salivary gland infection rates in the Tsetse fly have been found to rarely exceed 0.1% even in the endemic regions [46,47]. The tsetse fly bites the human host during the daytime when people are accidentally exposed to the diseases vectors while performing their regular duties in the riverine tsetse belts. The tsetse flies are also strongly attracted towards moving object [48]. Humans travelling on vehicles are therefore found to be more susceptible to tsetse bites [48]. This also implies that immobile, sick and bedridden host is complete dead end case and would never contribute to the transmission chain of sleeping sickness. Additionally, terminal stage of Sleeping sickness, which involves neurological issues, leads to complete immobility of the host, which is again detrimental to the transmission cycle of the disease. For a vector-‐borne disease in which the vector-‐host contact frequency is very low and the vector itself has low infectivity of as less as 0.1%, the mobility of the host becomes even more important. A very natural question that must be answered is that how does the sleeping sickness causing pathogen perpetuates given the fact that it is intrinsically virulent and it also cripples the host mobility in the terminal stages? As per the insights of vector ecology such pathogen can only survive by causing a chronic infection so that the reservoir host has transmissible parasites density in the blood for a broader time period. This strategy would ensure that the reservoir hosts contribute towards infecting new vectors and help the perpetuation of the disease. The pathogen therefore by causing chronic infection would also incur less cost from the death of the host, as the host would have already contributed towards the transmission cycle before his or her death. A mobile host with chronic transmissible parasitaemia is required for a vector that has very low infectivity, low density and low frequency of interaction with the host. This improvised model also challenges one of the Ewald’s idea that vector-‐borne disease circulating more in the human host would become virulent with time. The majority of the sleeping sickness in humans is caused by Trypanosoma brucei gambiense whereas Trypanosoma brucei rhodesiense mainly infects
animals [45]. Trypanosoma brucei rhodesiense, which has circulated less in the human population, kills the human host in months whereas the more prevalent and circulated Trypanosoma brucei gambiense takes years to do the same [45]. Based on this model I would like to argue that the virulent variant of sleeping sickness parasite that is transmitted by a vector of very low infectivity and low contact frequency couldn’t afford to kill the host early. The early death of the human host would drastically reduce the probabilities of new vector infections. This would also lead to collapse of the transmission cycle or least transmission benefits for the parasite. Parasitic variants that keep the human host alive for a longer period of time would certainly out-‐compete the ones that kill the host too early in this particular case. The frequency of interaction between the vector and the reservoir host in case of River blindness or Onchocerciasis is also very less [49]. This refined trade-‐off model is equally applicable for all those diseases, which are transmitted by sessile vectors with very limited dispersal like Aedes aegypti. The Sand fly vector responsible for transmission of Visceral leishmaniasis are weak fliers, travelling with a characteristic short hopping flight, and usually, disperse not more than a few hundred metres from their breeding sites [21]. Leishmaniasis very much like Dengue is asymptomatic in a majority of the cases [40]. However, there are no studies done as of yet to prove the role of asymptomatic cases in the transmission of visceral leishmaniasis. Mathematical modelling suggests that these asymptomatic carriers constitute a reservoir of parasites driving the epidemic [40], although their infectiousness to sand flies is not yet formally established. Based on this new refined trade-‐off model of virulence evolution I would like to hypothesize that the asymptomatic cases of leishmaniasis would turn out to be the major contributor in its transmission dynamics too. I wish that in future experimental studies would be undertaken to prove the role of asymptomatic subjects in the transmission dynamics of visceral leishmaniasis. This model can also be used for diseases that have a trade-‐off between transmission and virulence and are transmitted by the Culex mosquitoes. West Nile Virus is one of the arboviruses that are transmitted by Culex mosquitoes where this refined trade-‐off model can be used to come up with testable predictions [50,51]. The model can be also used to understand the epidemiology of lymphatic filariasis also transmitted by Culex Pipiens [52]. .
7. The most important refutable prediction of this new improvised model of Ewald:
The asymptomatic cases of most of the vector-‐borne diseases should play a far more important role in the transmission dynamics of the diseases compared to what is known as of now. I would suggest that the researchers involved in epidemiological studies of vector-‐borne diseases should also investigate and therefore vindicate the role of asymptomatic cases in overall epidemiology of the disease. I, however, believe that for a disease transmitted by Vectors having limited dispersal, low infectivity and low frequency of contact with the host, the role of asymptomatic humans in the transmission of the disease is going to be significantly higher.
8. The limitations of this improvised Ewalds’s trade-‐off model:
There have been multiple studies since 2009 that have confirmed the role of reservoir host movement in the transmission of dengue. Similar results from other regions in the world where dengue is prevalent might help to add more weightage to my claims. Though the evidence cited and available is in no way in sufficient. Virulence, as pointed out by Bull and Ebert, is a complex trait and there are multiple parameters involved into it [53]. In case of Dengue, the immune system of the host plays a significant role in the extreme but rare cases of Dengue Haemorrhagic fever and Dengue Shock Syndrome. The insights from this paper are based on the verified assumption that variants that reproduce more vigorously lead to more severe immune response and therefore lead to severe symptomatic Dengue cases that result in incapacitation of the host. I have not considered the case of secondary infections of the same host with a different dengue strains. The secondary dengue infections that lead to dengue shock syndrome and dengue hemorrhagic fever are rare. The secondary infections would not affect the predictions of this model in a major way.
9. Conclusions: I strongly believe in this famous quote of Albert Einstein i.e “The important thing is not to stop questioning” [54]. Sometimes a theory or a scientific model can be improved by questioning its fundamental assumptions. I have shown clearly in this paper that correcting the flawed assumptions in Ewald’s model actually results in a more robust framework. This new improved model that integrates vector ecology into Ewald’s conventional model of virulence evolution has much to offer towards understanding of infectious disease epidemiology. The model not only offers new predictions but also answers many of the puzzling questions that conventional model was not able to explain. I would like to suggest that
further field studies should focus on the relevant role of vector ecology in virulence evolution of other diseases too. Researchers involved in mathematical modelling of infectious diseases could improve their models by including variables related to vector ecology. In short, there lies a highly fertile ground for the researchers right at the intersection of vector ecology, host movement and virulence evolution. Time has served us with a wonderful opportunity and we must all must jump into it with full conviction.
Acknowledgements:
I would like to acknowledge the sincere support of Dr. Stephen Stearns for his suggestions on improvement of this manuscript. I would also like to acknowledge the constant support I received from my mentor Pushkar Ganesh Vaidya.
Conflict of Interest:
The author declares that he does not have any conflict of interest.
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