**1. Introduction**

*Brucella* is a Gram-negative facultative intracellular coccobacillus, responsible for brucellosis, a worldwide zoonotic disease that affects livestock, wildlife, and humans. Brucellosis remains endemic in many parts of the world, including the Middle East, Africa, Latin America, Central Asia, and several regions of the Mediterranean [1–4]. *Brucella melitensis*, *Brucella abortus,* and *Brucella suis* are the most important members of the genus because they are responsible for the human disease [5,6] and for significant economic losses in livestock [7,8], while *Brucella canis*, *Brucella neotomae*, and *Brucella ovis* display less or non-zoonotic potential [9]. Recently, many other species have been described in aquatic mammals (like *Brucella pinnipedialis* and *Brucella ceti*) and other wildlife such as *Brucella papionis*, *Brucella microti*, *Brucella inopinata,* and *Brucella vulpis* [10–16].

### *1.1. Brucellosis, a Zoonosis*

Humans are accidental hosts for *Brucella* and are mainly infected through direct contact with infected animals, inhalation of airborne agents, or by ingestion of contaminated dairy products [17]. Human-to-human transmission may occur by organ transplantation, blood transfusion, or vertical transmission via breastfeeding [18–22]. Human brucellosis is at the origin of many symptoms namely undulating fever, malaise, fatigue, and anorexia. If untreated, it may progress into a chronic phase, characterized by the appearance of severe complications like endocarditis, orchitis, spondylitis, osteomyelitis, arthritis, meningoencephalitis, and recurring febrile conditions [23–26].

In domestic animals, such as cattle, sheep, goats, and swine, major consequences include abortion and metritis in females, and orchiepididymitis and infertility in males [27], resulting in reduced fertility and a significant decline in milk production [28]. Animal brucellosis is highly contagious for both animals and humans, and cross-species transmission

**Citation:** González-Espinoza, G.; Arce-Gorvel, V.; Mémet, S.; Gorvel, J.-P. *Brucella*: Reservoirs and Niches in Animals and Humans. *Pathogens* **2021**, *10*, 186. https://doi.org/10.3390/ pathogens10020186

Academic Editor: Sergio Costa Oliveira Received: 14 January 2021 Accepted: 5 February 2021 Published: 9 February 2021

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of certain *Brucella* spp. exists [29]. Natural infection occurs by direct contact with infected animals or their secretions [30], like aborted fetuses and fetal membranes that contain large amounts of the bacteria [31].

### *1.2. Infection and Dissemination*

*Brucella* organisms enter into their host through the mucosal membranes of the respiratory and digestive tracts [32]. Once inside, local professional phagocytes such as macrophages, dendritic cells, and neutrophils internalize the bacteria and move to the closest draining lymph nodes following the normal sampling of the immune system. This leads to subsequent dissemination to the different organs of the reticuloendothelial system, including lungs, spleen, liver, and bone marrow [33]. In pregnan<sup>t</sup> animals, *Brucella* displays a strong tropism for placental trophoblasts [34–36] and also for mammary glands [37], in which it replicates extensively causing placentitis and abortion in the last trimester of pregnancy in ruminants [33]. In humans, brucellosis is a systemic infection and any organ can become infected, albeit with some predilection for joints and liver, and at lower levels for the brain and heart [38].

### *1.3. Acute and Chronic Infections*

Human brucellosis presents a broad range of clinical manifestations from asymptomatic to severe disease. When symptoms are present, the incubation period is 1–4 weeks, but sometimes it takes several months with or without signs and symptoms. According to the duration of the symptoms, human brucellosis is classified into three different phases: acute (initial, 2 months), sub-acute (2–12 months), and chronic (more than 12 months) [39,40]. When focusing on the chronic phase, patients fall into three more categories: relapse (with fever or high IgG antibody titers after antibiotics therapy), chronic localized infection (recurrence of infectious foci and intermittent fever for long periods of time), and delayed convalescence (persistence of some symptoms without fever or other objective signs) [41].

In animals, brucellosis comprises three phases: the onset of the infection or incubation period, when *Brucella* invades the host without any clinical symptoms; the acute phase, when the bacteria replicate actively and infection remains unapparent in most cases or first pathological signs arise; and the chronic phase, during which bacterial loads reach a plateau before decreasing and sporadic clinical symptoms become visible, the infection localizing in sexually mature animals in the reproductive system to produce epididymitis or orchitis in males, and placentitis and abortion in females. Susceptibility to infection in females increases during the late pregnancy stages (third trimester of gestation) [31,42]. There is no pyrexia like in humans and death is rare; infection is self-limiting most of the time and does not involve other systemic lesions, but for *Brucella suis* infection in swine. Clinical symptoms for the latter include spondylitis of the lumbar and sacral regions, arthritis, paralysis of hind limbs, lameness, and abscesses in tissues [42]. In any case, chronicity relies on the continuous shedding of *Brucella* from the mammary gland or reproductive organ secretions for a protracted period. Therefore, infertility, repetitive abortions, and premature stillborn ensure *Brucella*'s permanence in the environment and liability for dissemination.

The long incubation period and the absence of obvious clinical signs in infected animals and patients correlate with low activation of innate immunity [43]. *Brucella* has indeed modified its pathogen-associated molecular patterns (PAMPs) into less detectable molecules, opening a permissive immunological window to spread stealthily throughout the reticuloendothelial system and find its target host cells [44]. Then, invasion of target cells occurs thanks to specific molecular determinants that drive not only ingress [45] but also resistance to intracellular killing allowing *Brucella* to reach its intracellular replicative niche within professional and non-professional phagocytes [46]. Even if innate immunity first restrains *Brucella* proliferation, a Th1 response with IFNγ and IL-12 production is absolutely required to eradicate it, leading either to complete clearance of the bacteria or

to a chronic infection, which arises from the ability of *Brucella* to persist undetected for prolonged periods of time within its host reservoirs [44,47].

We propose that the intracellular replication niche conditions the basis for the establishment of the reservoirs in which *Brucella* persists inside its host. What is currently known of the suitable niches for *Brucella* infection in its various hosts and of the reservoirs of *Brucella* that support chronic infection?

### **2. Niche and Reservoir**
