Caitlin Clark English

Don’t Go Infecting My Heart

Breaking down the microbiology world one bite at a time

Don’t Go Infecting My Heart

Written by

Caitlin Clark

The roundworm Dirofilaria immitis is responsible for causing heartworm disease in canines. D. immitis is an obligate parasite, meaning it cannot survive outside of a host. Immature worms are ingested by a mosquito during a blood meal from an infected canine host, where they develop into an infective, immature larval stage. The infected mosquito then transmits this larvae into a new canine host during a blood meal. The worms quickly develop into adults that reside and mate in the pulmonary artery and right ventricle of the heart (leading to the lungs), and new immature worms will develop for the cycle to continue.1, 2

Life cycle of D. immitis, simplified, showing mosquito and canine stages. (Image created by the author in Clip Studio Paint)

Heartworm disease affects the cardiovascular system of the dog, with the adult worms causing impaired blood flow, hypoxia (low oxygen levels in the blood), and damage to the blood vessel cells, eventually leading to heart failure and sudden death.1 The immature worms circulating the blood can also cause renal dysfunction.2 While this parasite primarily targets dogs, it does have zoonotic potential. Humans can be infected with D. immitis, and though they currently remain asymptomatic, this may not always be the case.1 Thus, an understanding of how these parasites can survive so well in their host is necessary to better target them against infection, both in dogs and potentially in humans.

Like all parasites, D. immitis utilizes several methods to survive in the host. Excretory/secretory antigens, which are molecules produced by the parasite to help its overall survival in the host by modulating immune response, have been shown to promote vasodilation (widening blood vessels), regulate vascular remodeling (altering the structure and arrangement in blood vessels), and stimulate the angiogenic pathway.2,3

Angiogenesis is the process of forming new blood vessels from existing ones, and one of its most important regulators is the vascular endothelial growth factor isoform A, or VEGF-A. VEGF-A can bind to the receptor VEGFR-1 to decrease angiogenesis, or to VEGFR-2 to promote angiogenesis. Angiogenesis can also be stimulated by membrane endoglin (mEndoglin) or reduced by soluble endoglin (sEndoglin). Excessive angiogenesis could limit clot formation and white blood cell migration to tissues, as well as lead to blood vessel leakage.

In this study, Collado-Cuadrado and his team chose to investigate two particular excretory/secretory antigens: galectin (GAL) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) proteins, which had been previously shown to be involved in supporting D. immitis’s survival within its host. Their research looked to see what role, if any, might GAL and GAPDH play in regulating angiogenesis, which would further promote parasitic survival in the host.

In human cell cultures, the worm antigens GAL and GAPDH, in the presence of VEGF-A, showed a significant increase in the production of VEGF-A, VEGFR-2, and mEndoglin, all of which promote angiogenesis. In contrast, individual stimulation with the antigens or VEGF-A did not affect the production of these molecules. VEGF-A would initially simulate a hypoxic environment likely to be seen in an infected host, but it is clear that both VEGF-A and the antigens are necessary for stimulating these proangiogenic factors. This suggests that GAL and GAPDH promote angiogenesis in the presence of VEGF-A.

GAL and GAPDH, with or without VEGF-A, also showed no significant changes to the production of VEGFR-1 and sEndoglin, which reduce angiogenesis, further supporting that they stimulate angiogenesis in the host and do not promote antiangiogenic activity.

Treatment with the antigens in the presence of VEGF-A also showed a significant increase in cell proliferation, cell migration, and pseudocapillary formation, all of which are necessary steps in angiogenesis. In response to a hypoxic environment, endothelial cells (cells lining the blood vessels) will grow toward an angiogenic signal like VEGF-A, or in this case, VEGF-A and GAL or GAPDH.4 This in turn could promote the survival of the parasite in the blood vessels, though more research is needed to further understand this mechanism.5

Continued research into D. immitis and its mechanisms of survival within its canine host is extremely important. Some studies have begun to show evidence of strains of D. immitis that are resistant to the current preventative treatments for heartworm, resulting in dogs on consistent heartworm preventative to still be infected with the parasite.6

In addition, D. immitis can infect humans and is considered a public health concern. Though it is usually asymptomatic, more frequent reports of humans infected by D. immitis of ranging severity have emerged, such as infections beneath the skin or in the eye.7 Continuing to pursue different avenues of treatment and prevention are necessary to control this parasite for both humans and their canine companions. GAL and GAPDH might prove to be significant targets to reduce parasite survival within the host, offering new options for preventatives or treatments that can overcome developing resistance, and perhaps offer a plan of action should human infections persist. 

Link to the original post: Collado-Cuadrado M, Balmori-de la Puente A, Rodriguez-Escolar I, Infante González-Mohino E, Alarcón-Torrecillas C, Pericacho M, Morchón R. Glyceraldehyde 3-phosphate dehydrogenase and galectin from Dirofilaria immitis excretory/secretory antigens activate proangiogenic pathway in in vitro vascular endothelial cell model. Animals. 2025 Mar;15(7)964.

Additional Sources:

  1. Noack S, Harrington J, Carithers DS, Kaminsky R, Selzer PM. Heartworm disease – Overview, intervention, and industry perspective. Int J Parasitol Drugs Drug Resist. 2021 Apr 27;16:65-89. https://doi.org/10.1016/j.ijpddr.2021.03.004
  2. Cardona Machado CD, Alarcón-Torrecillas C, Perichacho M, Rodríguez-Escolar I, Carretón E, Montoya-Alonso JA, Morchón R. Involvement of the excretory/secretory and surface-associated antigens of Dirofilaria immitis adult worms in the angiogenic response in an in-vitro endothelial cell model. Vet Parasitol. 2023 Jun;318:109939. https://doi.org/10.1016/j.vetpar.2023.109939
  3. Rodríguez-Roisin R, Barberà JA. Pulmonary vessels. In: Barnes PJ, Drazen JM, Rennard SI, Thomson NC, editors. Asthma and COPD. 2nd ed. Academic Press; 2009 [accessed 2025 Apr 9]. 249-256. https://doi.org/10.1016/B978-0-12-374001-4.00020-1
  4. Adair TH, Montani JP. Overview of Angiogenesis. In: Adair TH, Montani JP. Angiogenesis. San Rafael (CA): Morgan & Claypool Life Sciences; 2010 [accessed 2025 Apr 9]. https://www.ncbi.nlm.nih.gov/books/NBK53238/
  5. Collado-Cuadrado M, Alarcón-Torrecillas C, Balmori-de la Puente A, Rodriguez-Escolar I, González-Mohino EI, Pericacho M, Morchón R. Angiogenesis as a survival mechanism in heartworm disease: the role of fructose-bisphosphate aldolase and actin from Dirofilaria immitis in an in vitro endothelial model. Animals. 2024 Nov;14(23):3371. https://doi.org/10.3390/ani14233371
  6. Bowman DD. Heartworms, macrocyclic lactones, and the specter of resistance to prevention in the United States. Parasit Vectors. 2012 Jul 9;5:138. https://doi.org/10.1186/1756-3305-5-138
  7. Simón F, Siles-Lucas M, Morchón R, González-Miguel J, Mellado I, Carretón E, Montoya-Alonso JA. Human and animal dirofilariasis: the emergence of a zoonotic mosaic. Clin Microbiol Rev. 20212 Jul 1. https://doi.org/10.1128/cmr.00012-12

Featured image: Created by the author with Clip Studio Paint