Written by Sebastiano Busato, Ph.D., Ruminant Associate Research Scientist
Adequate control of disease-causing pathogens is fundamental, as it can be key in reducing losses due to decreased production, increased culling and costly pharmaceutical protocols. The rise of novel viral pathogens in livestock, such as the recently detected cases of H5N1 Highly Pathogenic Avian Influenza (H5N1HPAI) in cattle, underscores the urgent need for advanced detection, robust biosecurity measures, and holistic control of pathogens.
HPAI in Cattle
Since its initial detection in livestock in March of this year, the disease has spread to several states in the Midwestern and Western USA, with 395 confirmed cases across 14 states as of October 29, 2024. While the full clinical impact of the disease is not yet fully known, producers have reported animals experiencing reduced feed intake and milk production, and abnormally thickened milk. Current reports indicate that bovine-to-bovine transmission spread within a herd can occur, and although most animals recover with supportive treatment, producers have seen an increase in mortality and culling rate as a result of the disease. Our firsthand conversations with producers suggest that, after the initial detection of the virus, the time needed for a herd to fully recover can vary substantially from one farm to another. This suggests that underlying health factors, as well as nutrition and management, likely play a role in the severity of the disease.
HPAI and coinfection
Relatively little is known about H5N1HPAI in cattle from a clinical research perspective. However, a considerable number of scientific studies conducted in poultry have reached a similar conclusion: the combined presence of a bacterial or protozoal pathogen (coinfection) within a bird worsens the symptoms, duration and shedding of HPAI. For example: coinfection of HPAI and Streptococcus aureus in chickens led to worse clinical outcomes, higher mortality and longer recovery time than HPAI alone [1]. Chickens challenged with a coinfection of mycoplasma and LPAI (a mild form of avian influenza, usually with minor to no clinical significance) displayed more internal lesions and weight gain reduction than those challenged with either pathogen alone [2]. Finally, coinfection of LPAI with E. coli led to a more sustained immune response, and more prolonged viral shedding when compared to chickens exposed to LPAI alone [3]. The mechanism behind these observations is not entirely clear, but it is thought that certain bacterial pathogens can “activate” the HPAI virus, via a series of proteins that they produce.
These findings are not entirely surprising: in a prior Dairy Herd Management article, we described how insights from our PathKinex™ microbial surveillance platform showed that 58% of cows exhibiting clinical disease harbor more than one pathogen, a state known as a coinfection. Also, disease incidence and severity heighten when more than one pathogen is present. Furthermore, we presented results from a study in collaboration with Dr. Federico Zuckermann at University of Illinois, who found that administration of ProVent ECL (a Bacillus subtilis-based probiotic) was successful in reducing pathogen load and lung lesion in a virus-bacteria coinfection model [4]. The authors suggested that the probiotic could modulate the immune response, thus enabling the animals to have a more robust response against the virus.
Exploring Pathogen Profiles in HPAI-Infected Herds
With the emergence of HPAI in US dairy herds, United Animal Health sought to understand what pathogen profiles of infected herds may reveal. We deployed our PathKinex™ pathogen surveillance platform, a novel microbial surveillance platform that detects and quantifies pathogens, and correlates to a variety of known production factors to gain greater resolution of the clinical picture. We selected two dairy herds in Texas and one in Midwest, all of which had either reported animals experiencing H5N1HPAI symptoms, or with confirmed H5N1 cases (Figure 1).
PathKinex Learnings from HPAI Infected Dairy Herds
While most bacterial markers did not differ between the healthy and sick animals included in the analysis, the prevalence of Fusobacterium necrophorum was 2-3 times higher in animals with HPAI within the Texas Herd (Figure 1A). Additionally, in one of the two dairy farms, sick animals had higher prevalence of Clostridium perfringens. On the other hand, while Fusobacterium levels did not differ within the Midwest herd, we detected a large increase in multiple virulence genes of E. coli (STa, stx1, stx2, eaeA and EAST1) and Salmonella (invA) between the period before detection of H5N1 HPAI and during the outbreak (Figure 1B).
Taken together, these results suggest that animals with pre-existing bacterial infections are more likely to display more disease symptoms from HPAI, in agreement with what has been reported for HPAI in poultry. Furthermore, these findings suggest that this increase in susceptibility to HPAI is not tied to a specific pathogen, and instead can be brought forth by a number of different microorganisms.
Figure 1. A) Prevalence of F. necrophorum in two Texas dairy herds with confirmed HPAI cases, from sampled animals that were either sick or healthy. B) Prevalence of major E. coli and Salmonella virulence genes from a Midwest dairy herd sampled in 2023 (before the appearance of HPAI) and in 2024 (after detection of HPAI). Abbreviations are as follows: STa = heat-stable enterotoxin; stx1 and stx2 = Shiga toxin 1 and 2; eaeA = enteroaggregative E. coli; EAST1 = heat-stable enterotoxin 1; invA = Salmonella invasion protein.
Probiotics and HPAI: future directions
While studies on H5N1 HPAI in dairy herds are still undergoing, recent studies have proven the effectiveness of United Animal Health’s Bacillus-based products against avian influenza in poultry. A study presented at the 22nd Congress of the World Veterinary Poultry Association in September 2023 treated broilers with either a conventional antibiotic or Novela ECL, a multistrain Bacillus-based product sold by United Animal Health [5]. Broilers receiving Novela ECL had improved weight gain and feed efficiency, and overall lower mortality, despite the presence of avian influenza and infectious bronchitis. The mortality was particularly high for those animals exposed to both viruses at once, which happened less frequently in the Bacillus-treated group. The authors argue that the Bacillus strains could modulate the immune response in broilers, which is supported by earlier studies in which administration of a Bacillus subtilis-based probiotic increased CD4+ and CD8+ T cell responses in a model of inactivated avian influenza [6].
Building resilience in response to multiple stressors is vital for protecting health and ensuring a strong response against HPAI. While there isn’t a single solution, using a combination of approaches to reduce pathogen load, enhance innate immunity, and maintain gut integrity should be considered. Visit UnitedAnH.com/CowHealth to see more insights from United Animal Health on coinfections and to learn more on United Animal Health probiotic solutions.
All statements are based on independent trials conducted by or in conjunction with United Animal Health. This product is not intended to diagnose, treat, cure, or prevent any disease.
References
[1] N. Kishida, Y. Sakoda, M. Eto, Y. Sunaga, and H. Kida, “Co-infection of Staphylococcus aureus or Haemophilus paragallinarum exacerbates H9N2 influenza A virus infection in chickens,” Arch Virol, vol. 149, no. 11, pp. 2095–2104, Nov. 2004, doi: 10.1007/s00705-004-0372-1.
[2] L. Stipkovits et al., “Pathologic lesions caused by coinfection of Mycoplasma gallisepticum and H3N8 low pathogenic avian influenza virus in chickens,” Vet Pathol, vol. 49, no. 2, pp. 273–283, Mar. 2012, doi: 10.1177/0300985811415702.
[3] S. Bano, K. Naeem, and S. A. Malik, “Evaluation of pathogenic potential of avian influenza virus serotype H9N2 in chickens,” Avian Dis, vol. 47, no. 3 Suppl, pp. 817–822, 2003, doi: 10.1637/0005-2086-47.s3.817.
[4] F. A. Zuckermann et al., “Bacillus-Based Direct-Fed Microbial Reduces the Pathogenic Synergy of a Coinfection with Salmonella enterica Serovar Choleraesuis and Porcine Reproductive and Respiratory Syndrome Virus,” Infection and Immunity, vol. 90, no. 4, pp. e00574-21, Mar. 2022, doi: 10.1128/iai.00574-21.
[5] M. Rady, A. Soliman, A. El-Tokhy, M. Badr, A. Zanaty, and N. Amarin, “Efficacy of a multi strain Bacillus subtilis and Bacillus pumilus probiotic given through drinking water on reducing mortality after H9N2 & IBV field infection,” presented at the XXII Congress of the WVPA, Verona, IT, Sep. 2023.
[6] J. E. Lee et al., “Bacillus subtilis spores as adjuvants against avian influenza H9N2 induce antigen-specific antibody and T cell responses in White Leghorn chickens,” Vet Res, vol. 51, no. 1, p. 68, May 2020, doi: 10.1186/s13567-020-00788-8.
