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PROJECT TOPIC: EFFECT OF TOLL–LIKE RECEPTOR7/8 AGONIST IMMUNISATION OF YOUNG CROSSBRED CATTLE ON INNATE IMMUNE STIMULATION AGAINST TICK– BORNE DISEASES

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CHAPTER ONE 1.0.0    INTRODUCTION 1.1.0    BACKGROUND

Livestock diseases transmitted by arthropod vectors impact a severe disease burden on small farmers in tropical countries where these diseases are endemic. In West Africa, the tick- borne diseases heartwater, babesiosis and anaplasmosis, together with the tick-associated skin disease dermatophilosis and tsetse-transmitted trypanosomiasis, have repeatedly frustrated attempts to increase animal productivity by genetic improvement of the indigenous cattle breeds through cross-breeding with exotic highly productive cattle (Aning, 1982; Uilenberg Gerrit, 1995; Bell-Sakyi et al., 1996; de Castro, 1997; Walker and Koney, 1999; Bell-Sakyi et al., 2004).

This disease burden has a disproportionate impact on resource-poor farmers due to the high cost of prevention using acaricides/insecticides and treatment of sick animals (De Castro, 1997; Minjauw and McLeod, 2003). However, the greatest impact results from the severity  of disease among higher producing dairy and dual-purpose breeds and crosses between these higher productivity breeds and indigenous cattle breeds with consequent loss of capacity to improve productivity (Simuunza et al., 2011). The world cost of Tick–borne diseases, in relation to death of animals, losses in production, treatment and control of ticks are projected to be between $13.9 billion and $18.7 billion yearly.

Importantly, effective control of tick-borne diseases in endemic regions requires control of a complex of pathogens rather than a single pathogen-disease entity. A separate vaccine targeting each pathogen is not feasible for a variety of reasons. Therefore, the most effective means of control is to use one intervention to target multiple pathogens (Frisch et al., 2000; Graf et al., 2004; Estrada – Peña and Salman, 2013; de la Fuente et al., 2017). Multiple

pathogens infection is commonplace in most tropical regions. Here, the pathogen strains and the associated biological vector are widely prevalent. This condition allows for continuous pathogen challenge by intermittent feeding behaviour of tick species resulting in two or more pathogens circulating in individual cattle. However, not all cattle became infected with multiple pathogens. Notably the indigenous cattle have demonstrated high level of resistance to clinical disease without the need for treatment (Nadelman et al., 1997; Alekseev et al. 2001; Bock et al., 2004; Nyarko et al., 2006) and this could be due to the fact that, the innate immune responses of these calves have evolved to provide some sort of protection for the local animals. The exotic and cross breeds on the other hand appear to lack this innate capability and are therefore unable to withstand infectious diseases challenge. To prevent high mortality rates associated with the production of the crossbred in the endemic tropical requires intensive use of drugs and acaricides at a high cost to the farmer. This genetic difference between the indigenous and crossbred cattle raises a key question whether the innate immune responses of the exotic and cross breeds can be induced by stimulation to allow these breeds survive mortality and also withstand multiple pathogen infections.

One potential means to achieve this goal is through stimulation of the innate immune system using synthetic version of TLR7 and 8. It is predicted that when calves were stimulated at young age will reduce or prevent disease while allowing for infection with the pathogen and the subsequent development of long-term adaptive immunity required for lifetime protection against death.

Innate immunity is responsible for protection against severe disease upon hemoparasitic infection in indigenous cattle breeds (Aguilar–Delfin et al., 2001; Beutler et al.,  2006; Ahmed et al., 2008; Bannerman et al., 2008a; Bannerman et al., 2008b). Babesia bovis is illustrative of this effect: in Friesian cattle, the parasite causes a high fever, severe anemia, neurologic disease (resembling cerebral malaria), and death within 10 days of infection, while

indigenous breeds show only mild disease. The time course (<10 days) points to innate immunity as the critical difference (Bock et al., 1997a; Bock et al; 1999a; Bock et al; 1999b; Goff et al., 2003; Bock et al; 2004; Brown et al., 2006; Bannerman et al., 2008a; Bannerman et al., 2008b; Carvalho et al., 2008;). This is supported by both laboratory studies showing induction of the innate immune response early in infection and, most importantly, by studies in which pre-treatment with mycobacterial-based adjuvants induce protection against severe disease (Aguilar–Delfin et al., 2001; Glass et al., 2005; Andersen et al., 2009). This innate immunity is reduced but not completely lost in exotic breeds, and that it can be induced is evident from studies with Babesia bovis (Goff et al., 2003). Cattle that survive the acute clinical disease phase remain persistently but asymptomatically infected and resistant to subsequent challenge with homologous or heterologous strains. The establishment of persistent infection actually functions as a live vaccine similar to that used to protect cattle in Israel, Australia and South Africa (Brown et al., 1999; Shkap et al., 2007). This pattern of asymptomatic persistent infection and protection holds for the other tick-borne pathogens (Peter et al., 1998; Barbour and Restrepo, 2000; Palmer et al., 2000).

Pathogens stimulate the innate immune response through Toll-like receptors that serve as sensors for pathogen molecules, including glycoproteins and carbohydrates, and therefore represent key initiators of innate immunity (Hajjar et al., 2002; Ibeagha et al., 2008; Ishii et al., 2008; Uematsu and Akira, 2008; Kumar et al., 2009). There is evidence that innate receptors can be stimulated by direct interaction with the agonists in humans, mice, and  cattle. The strategy in the present study was to target the bovine TLR-7 and TLR-8 by activation with the cognate agonists. TLR7 and  TLR8 typically recognize pathogen RNA  and synthetic agonists which are small amines (Diebold et al., 2004; Kawai and Akira, 2007; Severa and Fitzgerald, 2007; Miller et al., 2008) and activation with agonists induces secretion of both anti-microbial effectors and inflammatory cytokines (Severa and Fitzgerald,

2007; Miller et al., 2008). There is strong precedent for innate immunity stimulation that resulted in significant protection as compared to untreated cohorts based on studies using mycobacterial extracts in Bos indicus x Bos taurus calves (Tewari et al., 1996). However, whether protection can be induced by synthetic TLR agonists in the Friesian x Sanga F1 calves has not been tested but requires empirical data to resolve. One of the key questions regarding the effectiveness of our approach is whether injection with the synthetic TLR 7/8 agonist emulsion can stimulate the innate immune response in young crossbred calves. To answer this question, we evaluated the temperature, swelling of the draining pre-scapular lymph node, and secreted cytokines. Any significant shifts in these biologic indicators in response to immune stimulation are easy to measure on the field. Success with this approach will provide a low-cost disease control strategy that would be globally scalable for improvement of livestock productivity in tropical and subtropical regions.


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