COP28 Series: Climate Change and Health, Communicable Diseases
Vector-borne disease: tackling the spread of disease-carrying insects through biology
COP28 was the first of United Nations Climate Change Conference to feature a health programme, a welcome first given that the scientific community has been reporting the impact of climate change on our health for almost two decades. COP28’s ambitions to address the climate’s impact on our health were further demonstrated by the first Climate and Health Declaration signed by 123 countries, marking an international first in recognising the need to protect communities and prepare our healthcare systems to cope with climate-related health issues including extreme heat, air pollution and infectious diseases.
The relationship between climate change and human health is difficult to untangle, with clear evidence for some communicable diseases being driven by the changing climate. However, there are also more complex interactions at play, with human behaviour and ecological changes also impacting the spread of infectious diseases whilst being themselves influenced by climate changes.
Mosquitos and Ticks are the two top vectors for insect-borne diseases and their spread is one example where the interplay of climate change and the resulting consequences are challenging to resolve.
Mosquito-borne disease
Whilst predictions for the long term implications of malaria transmission differ between scientists it is becoming increasingly clear that the imminent effects of a changing climate are increasing the transmission rates of malaria. The longer summers and warmer winters now experienced across the world can extend the seasons typical for mosquitoes to live and breed, including Anopheles mosquito for which the females are the vectors of malaria.
As mosquito populations expand, the vector-borne disease burden is likely to increase and disease distribution expand. Evidence already exists that increasing temperatures expand the geographical areas that are suitable for mosquitoes, exposing immunologically naive populations to malaria, as well as other diseases carried by mosquitos such as Chikungunya, Dengue, Lymphatic filariasis, Rift Valley fever, Yellow Fever, Zika, Japanese encephalitis and West Nile fever. The Dengue, Chikungunya and Zika-carrying Aedes albopictus, for example, is expanding northwards and outwards in Europe.
Mosquito management and disease treatment is therefore going to become ever-more important. Some countries already have considerable experience in reducing malaria mortality and managing transmission. In Zambia, this progress is a result of improving case management, prompt diagnostics through use of rapid diagnostic tests and a large scale-up of malaria interventions through vector control measures including insecticide-treated nets and indoor residual spraying. These technologies are well established. However, the increasing use of insecticides on nets and in insect repellent has resulted in increasing resistance within the mosquito population reducing the effectiveness of these solutions.
To handle the increasing malaria infections rates alternative technologies are required. Public health solutions will likely require intervention at all levels: targeting mosquito populations themselves, as well as diagnosing and tackling the resulting disease through vaccines and therapy. Vector-borne disease prevention and therapy solutions traditionally receive less R&D attention than other diseases more prevalent in the Global North (and Dengue and Chikungunya are amongst those diseases denoted as ‘neglected tropical diseases’), so perhaps we will see an increase in R&D in the area as the threat from vector-borne disease grows.
Gene drives
One effective but controversial technique which can essentially wipe out a mosquito population takes advantage of the gene editing technology CRISPR. Gene drives are a technique by which a desired trait can be spread through populations faster than classical Mendelian inheritance allows.
A gene drive uses a transgenic construct that, once present in the genome on one chromosome (i.e. as a single ‘allele’), copies itself into the second chromosome thereby becoming changing heterozygous inheritance to a homozygous gene profile. In more detail, this is achieved by using a transgene which includes both the targeting guide RNA (gRNA) and the Cas9 enzyme, flanked either end by homology arms homologous to the site targeted by the gRNA. This means once the Cas9 is directed to the gene of interest and induces cleavage, the gRNA and Cas9 construct itself acts as the template for homology directed repair of the DNA break, thereby directing a copy of the transgene into the other DNA strand.
This gene technology has been utilised to target the gene doublesex (Agdsx) which encodes a male (AgdsxM) and female (AgdsxF) specific splice transcript. The female AgdsxF transcript includes exon 5 which is not present in the male AgdsxM transcript. When the coding sequence of exon 5 in the Agdsx gene is removed, only the AgdsxF transcript is disrupted. This means male mosquitos develop without any health impacts and remain fertile. In contrast, heterozygous female mosquitos develop into male mosquitos or develop to have both male and female morphological features (intersex phenotype). Homozygous females are completely sterile. When conducted in an enclosed lab environment, a CRISPR–Cas9 gene drive construct targeting intron 4/exon 5 of Agdsx spread rapidly and reached 100% prevalence within 7–11 generations while progressively reducing egg production to the point of total population collapse. This technology was protected by WO 2019243840, which is now a pending application in Europe, China and the US.
Whilst the potential to completely eradicate the Anopheles mosquitos would reduce the incidence of malaria through elimination of the vector, there are ethical and ecological concerns about the rapid, autonomous way that gene drives could eliminate a species. Careful consultation with input from the communities who will be most impacted will likely be necessary before this technology could be applied in the wild.
Fle-targeting
One alternative genetic approach that does not rely on a gene drive and instead induces confinable population suppression focuses on disrupting a female essential gene femaleless (fle) via CRISPR technology. The fle gene is required in female mosquitoes to suppress activation of dosage X chromosome compensation in females. In the absence of fle regulation, there is a lethal up-regulation of X chromosomes genes in females but no negative effect on males. In this technology transgenic lines were created that expressed the fle targeting guide RNAs (gRNAs) and combined with existing Cas9 transgenic lines to create male Fle+/Cas9+. The use of two sperate transgenic lines and no homology arms means that, unlike gene drive technology, the transgenic construct does not spread autonomously.
When Fle+/Cas9 male mosquitoes reproduce with female wildtype mosquitos the mosaic fle mutations induced in the offspring are enough to induce female lethality in the larval stages. With this approach, the fle mutation can be carried by male anopheline mosquitos and prevents any female progeny forming when crossing with wildtype female mosquitos. The next generation of male mosquitos pass on both CRISPR transgenes and fle alleles to subsequent generations, resulting in multigenerational daughter gynecide. This technology is further described in the pending International patent application WO 2023230572.
Tick-borne diseases
After mosquitoes, ticks are the second most significant vector with their geographical spread also being impacted by climate change. Lyme borreliosis is the bacterial species responsible for Lyme disease carried by ticks and the most common vector-borne disease in Europe. The Lyme borreliosis in Europe report commissioned by the WHO back in 2006 described the geographical spread of ticks through Europe to higher latitudes and altitudes as well as increasing densities of the tick population.
Increasing tick populations are not just problematic for human populations (where they are vectors for Lyme’s disease, the Babesia parasite and Flaviviridae viruses which cause Tickborne encephalitis) but also for domestic and wild animals. Ticks are vectors for Rickettsia spp. and Anaplasma ovis in Cypriot mouflons, Babesia spp. in gray kangaroos, Theileria, Anaplasma, Ehrlichia, and Babesia general wildlife, Borrelia burgdorferi in brown bears in Sweden, Borrelia spp. and Rickettsia spp. in mammals in Mongolia; and, a variety of tick-borne pathogens in raccoons, opossums, feral swine and white-tailed deer in the USA. An increase in geographical spread and population size increases the exposure to ticks and therefore increasing risk of tick borne diseases.
Education on awareness of tick disease and preventative measures is one approach to reduce the risk of tick-borne disease in humans that requires limited technical input. There appears to be limited appetite for developing similar genetic tools to control the tick population as seen for mosquitos. However, technology will play an increasing role in preventing disease in animals, both domestic and wild. Many a pet owner will be familiar with the responsibility of administering flea and tick treatments on a regular basis. US4933371 was a patent application filed back in 1988 directed to the use of linalool for flea and tick treatments. New patent applications for improved or alternative tick preventive compositions continue to be filed with pending International application WO 2022271961 focusing on the use of isoxazolin for controlling tick in felines. WO 2024097871 takes a slightly different approach for controlling tick infestations in cattle with a focus on developing vaccine for ticks, reducing the frequency of treatments required.
Effective preventative measures appear to be the current technical direction for handling the increasing tick risk, a drastically different approach to mosquitos.
The future of climate and vector-borne diseases
Whilst it is acknowledged that the interactions of climate change and vector-borne diseases carried by mosquitos and ticks are complicated there is an agreement in the scientific community that climate change is currently increasing the prevalence of vector-borne diseases. The disease burden from vector-borne disease looks set to increase over the coming decades, as vector populations spread to cover greater areas and populations which are unused to dealing with the pests. However, the scientific and wider community is yet to agree an approach for handling this emerging threat. There is a need for effective treatments and control of these vectors, without having detrimental impacts on the environment and bio-diversity. New technologies will play a central role in this frontier.
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